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Review

Exploring Immunological Effects and Novel Immune Adjuvants in Immunotherapy for Salivary Gland Cancers

by
Ryosuke Sato
1,†,
Hidekiyo Yamaki
1,†,
Hiroki Komatsuda
1,
Risa Wakisaka
1,
Takahiro Inoue
1,
Takumi Kumai
1,2,* and
Miki Takahara
1,2
1
Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa 0788510, Japan
2
Department of Innovative Head & Neck Cancer Research and Treatment, Asahikawa Medical University, Asahikawa 0788510, Japan
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2024, 16(6), 1205; https://doi.org/10.3390/cancers16061205
Submission received: 26 February 2024 / Revised: 12 March 2024 / Accepted: 17 March 2024 / Published: 19 March 2024
(This article belongs to the Special Issue Advances in Salivary Gland Carcinoma)
Browse Figure
Review Reports Versions Notes

Abstract

:

Simple Summary

The efficacy of immunotherapies in salivary gland cancer (SGC) remains controversial. To optimize immunotherapy, understanding the tumor microenvironment (TME) of SGC is necessary. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma exhibit immune-hot TME. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies have shown promising clinical efficacy of ICIs indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies. This review discusses the current understanding and future directions of immunotherapies for SGCs.

Abstract

Salivary gland cancer (SGC) is rare and comprises over 20 histological subtypes. Recently, clinical experience regarding immunotherapies for SGCs has been accumulating, yet their efficacy remains controversial. Understanding the tumor microenvironment (TME), including the expression of immune checkpoint molecules in SGC, is crucial to optimizing immunotherapy. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma generally exhibit immune-hot TME with high immune cell infiltration, frequent genetic mutations, and robust immune checkpoint molecule expression. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies showed promising clinical efficacy of ICIs, with an objective response rate ranging from 20.0–33.3%, indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies including anti-human epidermal growth factor receptor 2 and anti-androgen receptor therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies including chimeric antigen receptor-T therapy and cancer vaccines. This review discusses the current understanding and future directions of immunotherapies for SGCs, including ongoing clinical trials.

1. Introduction

Salivary gland cancer (SGC) is a rare type of cancer (0.6–1.4 per 100,000), accounting for less than 3% of all head and neck cancers [1]. According to the WHO classification of head and neck cancers in 2017 [2], SGCs originate from major or minor salivary glands and encompass more than 20 histological subtypes. Surgery remains the gold standard treatment for resectable SGCs, often followed by adjuvant radiotherapy for patients with positive surgical margins, lymph node metastases, or high-grade tumors. However, due to its rarity and diverse histology, there is no clinically established therapy for inoperable tumors, invasive local recurrences, or distant metastases [3]. Systemic chemotherapies have been investigated for the treatment of unresectable SGCs. Monotherapy with cytotoxic anticancer drugs such as cisplatin, paclitaxel, and vinorelbine has not demonstrated satisfactory clinical efficacy [4,5,6]. However, combinations of cytotoxic anticancer drugs have shown moderate clinical efficacy, with an objective response rate (ORR) ranging from 15% to 70% [7]. Recently, attention has turned to molecular-targeted therapies in light of advancements in the molecular biology of cancers. In salivary duct carcinoma (SDC), therapies targeting human epidermal growth factor receptor 2 (HER2) and androgen receptor (AR) have shown promising clinical efficacy [8]. Systemic chemotherapies, including molecular-targeted therapies, are generally used in patients with metastatic or recurrent SGCs [7], but their effectiveness as a first-line treatment remains to be elucidated.
Immunotherapy is a novel cancer therapy that harnesses the immune system of the body. Immune cells play an important role in recognizing and eliminating tumor cells based on tumor antigens. However, tumor cells can evade the immune system through various mechanisms, including the activation of negative immune checkpoints. Immune checkpoints are immunosuppressive molecules expressed on tumor and suppressive immune cells, enabling tumor immune evasion. Immune checkpoint inhibitors (ICIs) activate the self-immune system by blocking negative immune checkpoints, such as programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [9]. ICIs have been approved for multiple types of cancers extending the survival of patients with these cancers [10]. Recently, clinical experience with immunotherapies in SGCs has been accumulating. Some reports have shown promising clinical efficacy [11,12] while others have reported no response to ICIs in SGCs [13]. This discrepancy may be mediated by differences in the tumor microenvironment (TME) across histological types of SGCs. The TME, comprising tumor cells, immune cells, and cytokines, affects antitumor immunity and is pivotal in determining the clinical efficacy of immunotherapies [3]. Thus, understanding the TME differences among histological types of SGCs is important for enhancing immunotherapies in SGCs. Theocharis et al. [3] and Mueller et al. [8] have summarized the immune regulatory cells and immune checkpoint expression in SGC overall. This scoping review discusses unique topics including differences in the immunological backgrounds of representative histological types of SGCs, including mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (AdCC), and SDC. We also explore current evidence and future perspectives regarding checkpoint blockade and antigen-specific immunotherapies in SGCs.

2. Methods

This review referred to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) extension for scoping reviews [14]. The existing literature about the immunological background and the immunotherapies of SGCs was reviewed through PubMed and Google Scholar until January 2024. Two authors (R.S. and H.Y.) reviewed a selection of the literature. The search strategy was carried out by various combinations of terms: “salivary gland cancer”, “mucoepidermoid carcinoma”, “salivary duct carcinoma”, “adenoid cystic carcinoma”, “tumor microenvironment”, “immunotherapy”, “immune checkpoint”, and “programmed death ligand-1”. The review included not only clinical research but also an internal analysis of clinical trials, basic research, and case reports if the literature gave relevant information for the review. The literature not written in English was excluded.

3. The Immunological Background of Mucoepidermoid Carcinoma

MECs represent the most common histological subtype comprising 35% of the SGCs. MECs are classified as low-, intermediate-, or high-grade based on their histological type [15]. Although the prognosis of low-grade MEC is generally favorable after surgical resection, the 5-year survival rate of high-grade MEC is low, ranging from 0–43%, even with the multimodal treatment [16]. Suppression of antitumor immunity contributes to MEC progression compared to benign salivary gland tumors; MECs exhibit higher expression levels of several immune checkpoint molecules, including lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin, mucin domain-containing protein 3 (TIM3), and adenosine 2a receptor [17]. Knockdown of these immune checkpoint molecules prevents tumor progression in SGC mouse models, indicating that immune checkpoint molecules may support MEC growth. Abnormal angiogenesis by vascular endothelial growth factor (VEGF) in the TME initiates tumor formation and progression, partly via immune modulation [18]. VEGF is expressed in MEC regardless of histological grade, and inhibition of VEGF decreases tube formation in MEC cell lines [19]. VEGF-A expression correlates with the presence of tumor-associated macrophages (TAM) in patients with MEC [19]. As TAMs promote the migration and invasion ability of MEC cells [20], angiogenesis and TAMs cooperate to create an immunosuppressive TME conducive to MEC progression.
The immunogenicity of the TME in MEC varies across histological grades. The expression of programmed death ligand-1 (PD-L1) and human leukocyte antigen (HLA) positively correlates with histological grade [21]. Additionally, high-grade MEC exhibits a higher tumor mutational burden (TMB) than low-grade MEC [22]. Using RNA-sequencing analysis, Kang et al. reported that MEC with immune-hot TME exhibit activated immunity characterized by T-cell infiltration, cytolytic score, interferon-γ, antigen-presenting machinery, and immune modulator genes. Immune checkpoint molecules, including PD-L1, programmed death ligand-2 (PD-L2), T-cell immunoreceptors with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains, and CTLA-4, are abundantly expressed in MECs with immune-hot TME compared to those with immune-cold TME [23]. Among SGCs, MECs show higher immune cell infiltration in the TME, greater T-cell receptor diversity, and increased expression of HLA class I and II than that of AdCCs [24]. Given that MEC may represent an immunogenetic tumor type where immunotherapies could be effective (Figure 1), further research is necessary to examine the immunological differences in the TME across different histological grades of MEC.

4. The Immunological Background of Salivary Duct Carcinoma

SDC represents one of the most aggressive subtypes of SGCs, accounting for approximately 10% of cases, with high rates of local recurrence and distant metastasis [25,26]. About 20–59% of SDC arise from pleomorphic adenoma [26]. The prognosis of SDC is poor, with 5-year disease-free survival (DFS) and overall survival (OS) rates in the range of 42.5–52.7% and 34.1–41%, respectively [27,28]. SDC is considered a relatively immunogenic tumor with elevated immune cell infiltration and gene mutations. The immune-infiltrated subtype constitutes 64% of SDC cases [29]. RNA-sequencing studies have revealed increased T-cell infiltration and neoantigen expression in SDCs compared to that of myoepithelial carcinoma or AdCC [30]. In addition to immune cell infiltration, another study has shown that SDCs express high levels of T-cell receptor diversity and HLA class I/II [24]. However, multiple immunosuppressive mechanisms co-exist in the TME of SDCs. Despite upregulated CD8+ T-cell infiltration, the expression of immune checkpoint molecules, including FOXP3, PD-1, CTLA-4, and LAG-3, is associated with aggressive histological features of SDCs [28]. In a study involving 175 patients with SDC, Hirai et al. reported that 18% of patients were classified as PD-L1 positive (tumor proportion score ≥ 1%), and the positive PD-L1 expression was associated with worse progression-free survival (PFS) and OS in multivariate analysis [28]. Another study observed HLA class I downregulation in 82% of SDCs [31]. A high proportion of M2 TAM, known to suppress antitumor immunity, was observed in both the immune-hot and immune-cold TME of SDCs [29]. These TAMs expressed immune checkpoint molecules, including PD-L1, CD86, TIM-3, and galectin-9. Collectively, SDC represents an immune-hot tumor, but the coexistence of immunosuppressive TMEs may contribute to immune cell exhaustion and SDC progression.

5. The Immunological Background of Adenoid Cystic Carcinoma

AdCC accounts for approximately 10% of SGCs characterized by a slow growth but a high rate of distant metastasis [32,33]. Although the survival of patients with bone metastasis is poor, many patients with recurrent or metastatic AdCC, especially with pulmonary metastasis, survive for a long time due to an indolent clinical course. While radiation therapy (RT) is used for the targeted or palliative treatment of distant metastases, a large retrospective analysis indicated that radiotherapy does not improve OS [34]. Systemic chemotherapy has also failed to provide lasting benefits [6,35]. A critical aspect of AdCC is its immune-depleted TME. AdCC displays unfavorable immunogenic profiles for immunotherapies, including a T-cell exclusion phenotype, low immune cell infiltration and TMB, significant infiltration of M2 TAM and myeloid-derived suppressor cells, and HLA class I loss [30]. M2 TAM promotes AdCC proliferation via chemokines. The CCL2/CCR2 axis, a chemokine that modulates the TME, is involved in the recruitment and polarization of M2 TAM, and the overexpression of CCL2 is obviously associated with the poor prognosis of AdCC [36]. AdCC exhibits a low infiltration of immune cells, such as CD8+, granzyme B-positive tumor-infiltrating lymphocytes (TILs), CD1a+, and CD83+ cell populations [37]. Reduced numbers of CD8+ and CD1a+ cells in the TME are significantly associated with high recurrence rates and short survival [37] indicating that the immune desert TME may contribute to the progression of AdCC. Additionally, the expression of immune checkpoint proteins is low in patients with AdCC. Four out of six studies have shown no tissue PD-L1 expression in AdCCs [13,21,38,39,40,41]. Compared with other histological types, LAG3 expression in TIL and TP53 mutations in tumors are low in AdCC [42].
Besides TP53, other genetic mutations such as MYB-NFIB or MYBL1-NFIB fusions are observed in approximately 60% of AdCC [43,44,45]. MYB overexpression upregulates several neovascularization factors, including VEGF-A, fibroblast growth factor 2, and KIT, in AdCC [43]. Although the clinical benefits of multi-kinase inhibitors targeting these neovascularization factors are expected, monotherapies with these inhibitors have shown unsatisfactory results in AdCC [46,47,48,49,50,51]. Since multi-kinase inhibitors are known to regulate tumor immunity in other types of cancers [52], immunomodulation of the TME by these reagents remains unresolved in AdCC. Thus, the mutated AdCC proteins may act as immunogenic antigens. Several patients with metastatic AdCC have circulating T cells that recognize peptides associated with MYB-NFIB fusion [53]. The immune-cold TME in AdCC, characterized by low immune cell infiltration, frequency of mutations, and expression of immune checkpoint molecules (Figure 1), could be overcome by activating these mutation-reactive T cells.

6. The Expression Rates and Prognostic Ability of Immune Checkpoint Molecules in Salivary Gland Cancer

Like SDC, immune checkpoint molecules play an important role in the progression of SGC. Among the immune checkpoints, tissue expression of PD-L1 is the most investigated molecule as a poor prognostic and predictive factor for PD-1 inhibitors in various types of cancers [54]. The expression rates of PD-L1 in representative histological types of SGCs are summarized in Table 1 [21,28,31,38,39,40,41,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73]. Considering a cutoff point of ≥1% positive tumor cells, PD-L1 expression was observed in approximately 15–30% of SGCs [28,40,41,55,60,61,62,63,66,70,72,73]. Few studies showed high (>50%) [65,70] or no expression rates of PD-L1 [40]. PD-L1 positivity rates in SDC and adenocarcinoma not otherwise specified (adenocarcinoma NOS) are generally high ranging approximately 20–100% [28,31,55,56,62,67,71]. MEC showed moderately high PD-L1 positivity rates of approximately 10–80% [55,57,61,65,66,69,71,73]. The expression rate of PD-L1 in AdCC and acinic cell carcinoma was generally low [21,38,41,55,58,59,61,65,72]. Collectively, SDC, adenocarcinoma NOS, and MEC are possible candidates for treatment with PD-1 inhibitors.
In addition to other cancer types, positive PD-L1 expression may predict a poor prognosis in SGCs. Nine studies reported that positive PD-L1 expression was associated with poor prognosis in SGCs [28,31,55,58,61,64,65,69,71]. In contrast, seven studies reported no association between PD-L1 positivity and prognosis in SGCs [56,57,60,62,66,68,70]. Only one study reported a favorable prognosis for PD-L1-positive SGCs (low recurrence rate and prolonged DFS) [59]. The discrepancy between these studies might be explained by the histological types, PD-L1 scoring methods, cutoff points, and antibodies used to detect PD-L1. Further studies are required to standardize the method to detect PD-L1 expression and to apply PD-L1 as an accurate prognostic marker in SGCs. Wu et al. conducted a meta-analysis regarding the association between PD-L1 positivity and prognosis in SGCs [74]. This study revealed that high PD-L1 expression is associated with poor OS and DFS, indicating the importance of PD-L1 in SGC progression.
PD-L2, another ligand of PD-1, is also a prognostic factor in other types of cancers [75,76,77]. The positive expression rate of PD-L2 (58.7%) was higher than PD-L1 (25.4%) in SGCs [57]. Nakano et al. reported that PD-L2 expression is associated with reduced disease-specific survival and DFS in SGCs [60]. Interestingly, the expression of PD-L2 is observed in AdCC, whereas PD-L1 expression is usually negative [37,38]. Since infiltrated lymphocytes are positive for PD-1, the function of these lymphocytes may be suppressed via PD-L2 instead of PD-L1 in AdCC. Other negative immune checkpoints, including HLA-E and HLA-G, may also inhibit antitumor immunity against SGCs [21,37]. Lymphocytes express exhausted markers, such as CTLA-4 and LAG3, in the TME of SGCs [28,29,42].

7. The Clinical Efficacy of Immune Checkpoint Inhibitors in Salivary Gland Cancers

Being expressed in SGCs, negative immune checkpoints can be attractive targets to achieve tumor regression by releasing antitumor immunity. The clinical efficacy of ICIs in SGCs is summarized in Table 2 [11,12,13,72,78,79,80,81,82,83,84,85,86]. Generally, the clinical efficacy of ICI monotherapy is poor, with an ORR of less than 20% [13,72,78,79,80,82,83,85,86]. Although combination regimens with ICIs have been attempted in SGCs to improve their therapeutic effects, the results remain disappointing.
A combination of nivolumab and ipilimumab showed that ORR in AdCC and non-AdCC was 4% and 9%, respectively [86]. Another study with nivolumab and ipilimumab reported that the ORR of AdCC and non-AdCC was 6% and 16%, respectively [72]. Combination therapy with pembrolizumab and RT showed no objective response outside of the radiation treatment field [13]. Combining pembrolizumab with vorinostat, a histone deacetylase inhibitor, resulted in an ORR of 16% [81]. A phase II study of pembrolizumab with a vascularization inhibitor (lenvatinib) in AdCC failed to demonstrate superiority against the reported efficacy of lenvatinib monotherapy (ORR: 6%) [85]. Based on the promising ORR ranging from 16–42% in SGCs, mainly composed of SDC, by anti-androgen therapies [87,88,89], a multicenter phase II single-arm clinical trial with pembrolizumab and goserelin, which inhibit androgen production, is ongoing in the patients with AR-positive SGCs (NCT 03942653). Interim analysis of this study reported that the ORR, clinical benefit rate, and 6-month PFS were 22%, 88%, and 63%, respectively [90]. Although most ICI studies, including combination regimens, have failed to demonstrate clinical efficacy overall in SGCs, two clinical trials combining ICIs and cytotoxic chemotherapy are ongoing. NCT 03360890 is a phase II single-arm clinical trial investigating the clinical efficacy of pembrolizumab combined with docetaxel in SGCs and thyroid cancer. Another phase II single-arm clinical trial using pembrolizumab combined with pemetrexed for SGCs is ongoing (NCT 04895735).
As described in the previous section, the expression of PD-1 varies among the histological types of SGCs. We previously reported a promising ORR (33.3%) with PD-1 inhibitors in patients with high-grade SGCs, including SDC and high-grade MEC that express PD-1 [11]. Aggressive histological types of SGCs have been reported to show high-PD-L1 expression and TMB, which are positive predictive factors for the favorable clinical efficacy of PD-1 inhibitors [66,91,92]. AdCC is characterized by an immune-cold TME and negative PD-L1 expression. As expected, the ORRs for ICIs in AdCC were poor, in the range of 4.0–8.7% [72,78,85,86]. Since immune checkpoint-negative SGCs may be unresponsive to ICIs, it is rational to recruit patients with PD-L1- or PD-L2-positive SGCs for treatment with PD-1 inhibitors. Even et al. reported that the ORR for pembrolizumab was higher in PD-L1-positive (10.7%) compared to PD-L1-negative SGCs (2.6%) [83]. As several studies have reported promising ORRs of 20.0–33.3% [11,12,84], the appropriate selection of patients based on histological types and biomarkers, including PD-L1 and PD-L2, may improve the insufficient clinical efficacy of ICIs in SGCs.

8. Target-Specific Immunotherapy against Salivary Gland Cancers

A drawback of ICIs is their non-specific activation of immune cells. Autoimmune T cells activated by ICIs cause immune-related adverse effects. Tumor-specific immunotherapies are designed to avoid the risk of autoimmunity by targeting specific proteins expressed in tumor cells but not in normal cells [93]. To establish tumor-specific immunotherapy, the identification of tumor-derived molecules is necessary. Targeted therapies against specific molecules expressed in tumor cells have been investigated in SGCs. Inhibitors of AR, HER2, and neurotrophic tyrosine receptor kinases have shown promising clinical efficacy in patients with SDC and secretory carcinoma [94]. Among the targeted therapies, monoclonal antibodies bind to specific proteins on the tumor surface and exhibit therapeutic effects by blocking tumor growth signals. Moreover, the antitumor efficacy of monoclonal antibodies partly depends on natural killer cells, known as antibody-dependent cellular cytotoxicity [9,95]. Because the expression of HER2 is generally high in patients with SDC and adenocarcinoma NOS [59], anti-HER2 monoclonal antibody (trastuzumab) combined with docetaxel showed excellent ORR ranging from 60–72% in patients with SDC [96,97,98]. The epidermal growth factor receptor (EGFR) is expressed in various histological types of SGCs [59,94]. Despite some studies with anti-EGFR therapies not showing clinical efficacy against SGCs [99,100,101], we reported that the anti-EGFR monoclonal antibody (cetuximab) combined with paclitaxel demonstrated a preferable ORR of 71.4% in the patients with SGCs mainly composed of SDC [102].
These therapeutic antibodies can be used to establish chimeric antigen receptor (CAR) T cells, which is a mode of target-specific immunotherapy. CAR T cells are patient-derived T cells genetically transduced with Fab regions of tumor-reactive antibodies. The efficacy of CAR T-cell therapy has been demonstrated in hematologic malignancies, for which CD19-targeting CAR T-cell therapies have been approved by the U.S. Food and Drug Administration [9]. Invariant natural killer T cells transduced with mesothelin-targeting CAR are cytotoxic against mesothelin-expressing cancer cell lines, including SGC cells [103]. Prostate-specific membrane antigen (PSMA)-targeting CAR T-cell therapy decreases serum prostate-specific antigen levels in prostate cancer, indicating the feasibility of CAR T-cell therapy in solid tumors [104,105,106]. PSMA is a target of CAR T cells, antibody drug conjugates, and bi-specific T-cell-directed therapy in prostate cancer. In addition to prostate cancer, PSMA is expressed in SGCs such as AdCC. The studies on immunohistochemistry and PSMA/positron emission tomography revealed that the positivity rates of PSMA in AdCC were 94% and 93%, respectively [107,108]. The study on radioligand therapy by 177Lu-EB- PSMA-617 shows promising clinical response [109,110], suggesting that PSMA could be a targetable antigen in immunotherapy against AdCC. A phase I clinical trial of PSMA-targeting CAR T-cell therapy for patients with SGC or prostate cancer is ongoing (NCT 04249947). Phase I clinical trials with HER2-targeting CAR T-cell and CAR-macrophage therapies have recruited patients with HER2-positive solid tumors (NCT 04511871, 04660929, 06241456, and 06254807). As the safety of HER2-targeting CAR T-cell therapy has been confirmed [111], this treatment would be an interesting approach for SDC, most of which express HER2.
The requirements of ex vivo transduction and the expansion of T cells in the laboratory are major hurdles in applying CAR T therapy to a broad population of patients. Furthermore, the benefits of time-consuming and expensive CAR T-cell therapy can be easily impaired because of tumor heterogeneity and antigen loss [103,104]. Cancer vaccines are promising tumor-targeting immunotherapies that induce tumor-reactive T cells in patients by administering antigens and adjuvants. Because there is no need for expensive genetic transduction and T-cell expansion ex vivo, it is relatively simple to switch antigens in cancer vaccines compared to CAR T therapy, in situations of antigen loss. An enormous number of epitopes derived from tumor-derived antigens have been identified as vaccine sources [93]. After vaccine administration, these epitopes bind to HLA molecules on antigen-presenting cells, followed by the expansion of tumor-reactive T cells. Wilm’s tumor gene 1 (WT1) is a tumor-associated antigen (TAAs) that is overexpressed in tumors compared to normal tissues. Cancer vaccines with WT1-derived epitopes have been investigated in several types of cancers including SGCs [112,113,114]. In carcinoma ex pleomorphic adenoma, peptide-based WT1-targeting vaccines increased CD8+ T cells recognizing the WT1-derived peptide [113]. Another study reported that a WT1-targeting vaccine suppressed tumor growth for one year in recurrent AdCC [114].
In addition to TAAs, recent advances in genetic sequencing have enabled the detection of tumor-specific antigens (TSA) that are expressed only in tumor cells. TSA is considered an ideal cancer vaccine target because of its high immunogenicity and low cross-reactivity with normal tissues [93]. Neoantigens are TSAs generated by mutations in tumor cells. Cancer vaccines against neoantigens show promising clinical efficacy against several types of cancers [115,116,117,118]. The genetic sequences of SGCs revealed that SDC had a more abundant expression of neoantigens than other histological types of SGC, indicating that patients with SDC would benefit from cancer vaccines targeting neoantigens [30,92]. As a proof of concept, a patient with metastatic SDC achieved a complete response using a combination approach of a neoantigen-based dendritic cell vaccine and nivolumab [119]. AdCC is an unfavorable target for neoantigen-based vaccines because of its low mutational burden. Since it is difficult to conduct clinical trials in SGC owing to its rarity, clinical trials regarding neoantigen-based cancer vaccines are ongoing in solid tumors. Two clinical trials are investigating the efficacy of peptide- and mRNA-based neoantigen vaccines combined with pembrolizumab in patients with solid tumors (NCT 05198752 and 05269381). Because some SGCs overexpress neoantigens, the results of these trials would support the establishment of a TSA-targeting vaccine for SGC.

9. Conclusions and Future Directions

In this review, we summarize the current knowledge regarding the immune microenvironment in SGC. Although the clinical efficacy of ICI monotherapy is unacceptable, the optimization of combination therapies, such as multi-kinase inhibitors and RT, is promising for enhancing antitumor immunity by modifying the TME in SGCs. Lenvatinib is a multi-kinase inhibitor that targets VEGFR2 and VEGFR3. Interestingly, the inhibition of VEGF/VEGFR signaling reduces the number of regulatory T cells and increases that of cytotoxic T cells in hepatocellular carcinoma [120]. In a mouse model, lenvatinib with an anti-PD-1 antibody activated CD8+ T cells by reducing TAMs and activating the interferon pathway in multiple types of cancer cell lines [121]. Although the impact of multi-kinase inhibitors on the TME in SGC has not been determined, VEGF is expressed in MEC and immune-cold AdCCs [122,123] suggesting that multi-kinase inhibitors have the potential to augment the therapeutic efficacy of immunotherapy in SGCs. RT is also considered a candidate for combination therapy with immunotherapies. In addition to its direct tumor cytotoxicity through free radical-mediated DNA damage, the immunomodulatory effects of RT on the TME have been revealed in various types of cancers [124]. In AdCC, RT increased both the number of CD8+ lymphocytes and the ratio of CD8+/FoxP3+ regulatory T cells in the TME [38]. One case report described that low-dose RT combined with anti-PD-1 therapy resulted in long-standing stable disease in a patient with recurrent AdCC [125]. In contrast, another study reported the immunosuppressive effect of RT by decreasing the CD4+/regulatory T-cell ratio in AdCCs [126]. Further research is required to confirm the immunomodulatory effects of RT on the TME of SGC.
Establishing firm evidence for treatment strategies through clinical trials is difficult in rare types of cancer, including SGCs. Since the clinical evidence of chemotherapy is scarce in SGC, the combination of HER2-targeting antibody (trastuzumab) and docetaxel has shown favorable clinical responses with 70% of ORR [96]. Because trastuzumab is based on the IgG1 subclass, antitumor activity via antibody-dependent cellular cytotoxicity is expected. Docetaxel has shown synergy with a Th1-skewed cytokine [127] and a tumor antigen-based vaccine [128] in preclinical models. In a phase II trial of prostate cancer, docetaxel showed a synergistic effect with a cancer vaccine [129]. Thus, the combination of trastuzumab and docetaxel, which has been clinically approved as an efficient chemotherapy for SGC, may be an interesting adjuvant for immunotherapy. Although many clinical trials of cancer vaccines have been conducted, their outcomes have been unfavorable [93]. These poor results can be partly explained by the inadequate selection of adjuvants. To improve the effects of immunotherapy in SGC, further research is necessary to examine the immunologic effects of current treatments, identify novel immune adjuvants, such as pattern recognition receptor ligands [130], and establish cell lines from each histological subtype of SGCs.

Author Contributions

Conceptualization, T.K. and M.T.; writing—original draft preparation, R.S., H.Y., H.K., R.W. and T.I.; writing—review and editing, T.K. and M.T.; supervision, T.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by JSPS KAKENHI Grant Numbers 22K09659, 23K08977, and 23K08929.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The figure was created with BioRender.com. (https://www.biorender.com/, accessed on 29 January 2024. The authors thank Hajime Kamada (Hokuto Social Medical Corporation) for his excellent suggestions for the manuscript.

Conflicts of Interest

No potential conflicts of interest have been disclosed by the authors.

Abbreviations

AdCCAdenoid cystic carcinoma
ARAndrogen receptor
CARChimeric antigen receptor
CTLA-4Cytotoxic T-lymphocyte-associated protein 4
DFSDisease-free survival
EGFREpidermal growth factor receptor
HER2Human epidermal growth factor receptor 2
HLAHuman leukocyte antigen
ICIsImmune checkpoint inhibitors
LAG3Lymphocyte activation gene 3
MECMucoepidermoid carcinoma
NOSNot otherwise specified
ORRObjective response rate
OSOverall survival
PD-1Programmed death receptor-1
PD-L1Programmed death ligand-1
PD-L2Programmed death ligand-2
PFSProgression-free survival
PSMAProstate-specific membrane antigen
RTRadiation therapy
SDCSalivary duct carcinoma
SGCSalivary gland cancer
TAATumor-associated antigen
TAMTumor-associated macrophage
TILsTumor infiltrating lymphocytes
TIM3T-cell immunoglobulin and mucin domain-containing protein 3
TMBTumor mutational burden
TMETumor microenvironment
TSATumor-specific antigen
VEGFVascular endothelial growth factor
WT1Wilm’s tumor gene 1

References

  1. Jang, J.Y.; Choi, N.; Ko, Y.H.; Chung, M.K.; Son, Y.I.; Baek, C.H.; Baek, K.H.; Jeong, H.S. Treatment outcomes in metastatic and localized high-grade salivary gland cancer: High chance of cure with surgery and post-operative radiation in T1-2 N0 high-grade salivary gland cancer. BMC Cancer 2018, 18, 672. [Google Scholar] [CrossRef] [PubMed]
  2. Ihrler, S.; Guntinas-Lichius, O.; Haas, C.; Mollenhauer, M. Updates on tumours of the salivary glands: 2017 WHO classification. Pathologe 2018, 39, 11–17. [Google Scholar] [CrossRef] [PubMed]
  3. Theocharis, S.; Tasoulas, J.; Masaoutis, C.; Kokkali, S.; Klijanienko, J. Salivary gland cancer in the era of immunotherapy: Can we exploit tumor microenvironment? Expert. Opin. Ther. Targets 2020, 24, 1047–1059. [Google Scholar] [CrossRef] [PubMed]
  4. Licitra, L.; Marchini, S.; Spinazzè, S.; Rossi, A.; Rocca, A.; Grandi, C.; Molinari, R. Cisplatin in advanced salivary gland carcinoma. A phase II study of 25 patients. Cancer 1991, 68, 1874–1877. [Google Scholar] [CrossRef]
  5. Gilbert, J.; Li, Y.; Pinto, H.A.; Jennings, T.; Kies, M.S.; Silverman, P.; Forastiere, A.A. Phase II trial of taxol in salivary gland malignancies (E1394): A trial of the Eastern Cooperative Oncology Group. Head Neck 2006, 28, 197–204. [Google Scholar] [CrossRef]
  6. Airoldi, M.; Pedani, F.; Succo, G.; Gabriele, A.M.; Ragona, R.; Marchionatti, S.; Bumma, C. Phase II randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies. Cancer 2001, 91, 541–547. [Google Scholar] [CrossRef] [PubMed]
  7. Lewis, A.G.; Tong, T.; Maghami, E. Diagnosis and Management of Malignant Salivary Gland Tumors of the Parotid Gland. Otolaryngol. Clin. N. Am. 2016, 49, 343–380. [Google Scholar] [CrossRef]
  8. Mueller, S.K.; Haderlein, M.; Lettmaier, S.; Agaimy, A.; Haller, F.; Hecht, M.; Fietkau, R.; Iro, H.; Mantsopoulos, K. Targeted Therapy, Chemotherapy, Immunotherapy and Novel Treatment Options for Different Subtypes of Salivary Gland Cancer. J. Clin. Med. 2022, 11, 720. [Google Scholar] [CrossRef]
  9. Liu, C.; Yang, M.; Zhang, D.; Chen, M.; Zhu, D. Clinical cancer immunotherapy: Current progress and prospects. Front. Immunol. 2022, 13, 961805. [Google Scholar] [CrossRef]
  10. Kyi, C.; Postow, M.A. Immune checkpoint inhibitor combinations in solid tumors: Opportunities and challenges. Immunotherapy 2016, 8, 821–837. [Google Scholar] [CrossRef]
  11. Sato, R.; Kumai, T.; Ishida, Y.; Yuasa, R.; Kubota, A.; Wakisaka, R.; Komatsuda, H.; Yamaki, H.; Wada, T.; Harabuchi, Y. The efficacy of PD-1 inhibitors in patients with salivary gland carcinoma: A retrospective observational study. Laryngoscope Investig. Otolaryngol. 2022, 7, 1808–1813. [Google Scholar] [CrossRef]
  12. Ueda, Y.; Okano, S.; Enokida, T.; Fujisawa, T.; Ito, K.; Sato, M.; Tanaka, H.; Wada, A.; Tahara, M. Nivolumab for recurrent or metastatic head and neck cancer patients with non-squamous cell carcinoma and/or a primary subsite excluded from CheckMate141, a retrospective study. Oral Oncol. 2022, 130, 105932. [Google Scholar] [CrossRef]
  13. Mahmood, U.; Bang, A.; Chen, Y.H.; Mak, R.H.; Lorch, J.H.; Hanna, G.J.; Nishino, M.; Manuszak, C.; Thrash, E.M.; Severgnini, M.; et al. A Randomized Phase 2 Study of Pembrolizumab with or without Radiation in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2021, 109, 134–144. [Google Scholar] [CrossRef] [PubMed]
  14. Tricco, A.C.; Lillie, E.; Zarin, W.; O’Brien, K.K.; Colquhoun, H.; Levac, D.; Moher, D.; Peters, M.D.J.; Horsley, T.; Weeks, L.; et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann. Intern. Med. 2018, 169, 467–473. [Google Scholar] [CrossRef]
  15. Assar, S.; Assar, S.; Mardanifard, H.A.; Jaafari-Ashkavandi, Z. Salivary Gland Tumors in Iran: A Systematic Review of 2870 Cases Based on the New WHO Classification. Iran. J. Pathol. 2023, 18, 1–11. [Google Scholar] [CrossRef] [PubMed]
  16. Zhang, M.H.; Hasse, A.; Carroll, T.; Pearson, A.T.; Cipriani, N.A.; Ginat, D.T. Differentiating low and high grade mucoepidermoid carcinoma of the salivary glands using CT radiomics. Gland Surg. 2021, 10, 1646–1654. [Google Scholar] [CrossRef]
  17. Zhang, M.J.; Wu, C.C.; Wang, S.; Yang, L.L.; Sun, Z.J. Overexpression of LAG3, TIM3, and A2aR in adenoid cystic carcinoma and mucoepidermoid carcinoma. Oral Dis. 2023, 29, 175–187. [Google Scholar] [CrossRef] [PubMed]
  18. Tamura, R.; Tanaka, T.; Akasaki, Y.; Murayama, Y.; Yoshida, K.; Sasaki, H. The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: Perspectives for therapeutic implications. Med. Oncol. 2019, 37, 2. [Google Scholar] [CrossRef] [PubMed]
  19. Shieh, Y.S.; Hung, Y.J.; Hsieh, C.B.; Chen, J.S.; Chou, K.C.; Liu, S.Y. Tumor-associated macrophage correlated with angiogenesis and progression of mucoepidermoid carcinoma of salivary glands. Ann. Surg. Oncol. 2009, 16, 751–760. [Google Scholar] [CrossRef] [PubMed]
  20. Chiu, K.C.; Lee, C.H.; Liu, S.Y.; Yeh, C.T.; Huang, R.Y.; Yuh, D.Y.; Cheng, J.C.; Chou, Y.T.; Shieh, Y.S. Protumoral effect of macrophage through Axl activation on mucoepidermoid carcinoma. J. Oral Pathol. Med. 2014, 43, 538–544. [Google Scholar] [CrossRef]
  21. Mosconi, C.; Arantes, D.A.C.; Goncalves, A.S.; Alencar, R.C.G.; Oliveira, J.C.; Silva, T.A.; Mendonca, E.F.; Batista, A.C. Immunohistochemical investigations on the expression of programmed cell death ligand 1, human leukocyte antigens G and E, and granzyme B in intraoral mucoepidermoid carcinoma. Arch. Oral Biol. 2017, 83, 55–62. [Google Scholar] [CrossRef]
  22. Nagatani, Y.; Kiyota, N.; Imamura, Y.; Koyama, T.; Funakoshi, Y.; Komatsu, M.; Teshima, M.; Nibu, K.-I.; Sakai, K.; Nishio, K.; et al. Abstract 6143: Tumor immune microenvironment in salivary gland cancer. Cancer Res. 2022, 82, 6143. [Google Scholar] [CrossRef]
  23. Kang, H.; Seo, M.K.; Park, B.; Yoon, S.O.; Koh, Y.W.; Kim, D.; Kim, S. Characterizing intrinsic molecular features of the immune subtypes of salivary mucoepidermoid carcinoma. Transl. Oncol. 2022, 24, 101496. [Google Scholar] [CrossRef]
  24. Hong, J.; Choi, E.; Kim, D.; Seo, M.K.; Kang, H.; Park, B.; Kim, S. Immunological subtyping of salivary gland cancer identifies histological origin-specific tumor immune microenvironment. NPJ Precis. Oncol. 2024, 8, 15. [Google Scholar] [CrossRef] [PubMed]
  25. Gilbert, M.R.; Sharma, A.; Schmitt, N.C.; Johnson, J.T.; Ferris, R.L.; Duvvuri, U.; Kim, S. A 20-Year Review of 75 Cases of Salivary Duct Carcinoma. JAMA Otolaryngol. Head Neck Surg. 2016, 142, 489–495. [Google Scholar] [CrossRef]
  26. Nakaguro, M.; Tada, Y.; Faquin, W.C.; Sadow, P.M.; Wirth, L.J.; Nagao, T. Salivary duct carcinoma: Updates in histology, cytology, molecular biology, and treatment. Cancer Cytopathol. 2020, 128, 693–703. [Google Scholar] [CrossRef] [PubMed]
  27. Stodulski, D.; Mikaszewski, B.; Majewska, H.; Kuczkowski, J. Parotid salivary duct carcinoma: A single institution’s 20-year experience. Eur. Arch. Otorhinolaryngol. 2019, 276, 2031–2038. [Google Scholar] [CrossRef] [PubMed]
  28. Hirai, H.; Nakaguro, M.; Tada, Y.; Saigusa, N.; Kawakita, D.; Honma, Y.; Kano, S.; Tsukahara, K.; Ozawa, H.; Okada, T.; et al. Prognostic value and clinicopathological roles of the tumor immune microenvironment in salivary duct carcinoma. Virchows Arch. 2023, 483, 367–379. [Google Scholar] [CrossRef] [PubMed]
  29. Alame, M.; Cornillot, E.; Cacheux, V.; Tosato, G.; Four, M.; De Oliveira, L.; Gofflot, S.; Delvenne, P.; Turtoi, E.; Cabello-Aguilar, S.; et al. The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities. Theranostics 2020, 10, 4383–4394. [Google Scholar] [CrossRef] [PubMed]
  30. Linxweiler, M.; Kuo, F.; Katabi, N.; Lee, M.; Nadeem, Z.; Dalin, M.G.; Makarov, V.; Chowell, D.; Dogan, S.; Ganly, I.; et al. The Immune Microenvironment and Neoantigen Landscape of Aggressive Salivary Gland Carcinomas Differ by Subtype. Clin. Cancer Res. 2020, 26, 2859–2870. [Google Scholar] [CrossRef] [PubMed]
  31. Xu, B.; Jungbluth, A.A.; Frosina, D.; Alzumaili, B.; Aleynick, N.; Slodkowska, E.; Higgins, K.; Ho, A.; Morris, L.; Ghossein, R.; et al. The immune microenvironment and expression of PD-L1, PD-1, PRAME and MHC I in salivary duct carcinoma. Histopathology 2019, 75, 672–682. [Google Scholar] [CrossRef]
  32. Laurie, S.A.; Ho, A.L.; Fury, M.G.; Sherman, E.; Pfister, D.G. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: A systematic review. Lancet Oncol. 2011, 12, 815–824. [Google Scholar] [CrossRef]
  33. Fang, Y.; Peng, Z.; Wang, Y.; Gao, K.; Liu, Y.; Fan, R.; Zhang, H.; Xie, Z.; Jiang, W. Current opinions on diagnosis and treatment of adenoid cystic carcinoma. Oral Oncol. 2022, 130, 105945. [Google Scholar] [CrossRef] [PubMed]
  34. Lloyd, S.; Yu, J.B.; Wilson, L.D.; Decker, R.H. Determinants and patterns of survival in adenoid cystic carcinoma of the head and neck, including an analysis of adjuvant radiation therapy. Am. J. Clin. Oncol. 2011, 34, 76–81. [Google Scholar] [CrossRef] [PubMed]
  35. Licitra, L.; Cavina, R.; Grandi, C.; Palma, S.D.; Guzzo, M.; Demicheli, R.; Molinari, R. Cisplatin, doxorubicin and cyclophosphamide in advanced salivary gland carcinoma. A phase II trial of 22 patients. Ann. Oncol. 1996, 7, 640–642. [Google Scholar] [CrossRef] [PubMed]
  36. Yang, Z.; Li, H.; Wang, W.; Zhang, J.; Jia, S.; Wang, J.; Wei, J.; Lei, D.; Hu, K.; Yang, X. CCL2/CCR2 Axis Promotes the Progression of Salivary Adenoid Cystic Carcinoma via Recruiting and Reprogramming the Tumor-Associated Macrophages. Front. Oncol. 2019, 9, 231. [Google Scholar] [CrossRef] [PubMed]
  37. Mosconi, C.; de Arruda, J.A.A.; de Farias, A.C.R.; Oliveira, G.A.Q.; de Paula, H.M.; Fonseca, F.P.; Mesquita, R.A.; Silva, T.A.; Mendonca, E.F.; Batista, A.C. Immune microenvironment and evasion mechanisms in adenoid cystic carcinomas of salivary glands. Oral Oncol. 2019, 88, 95–101. [Google Scholar] [CrossRef] [PubMed]
  38. Sridharan, V.; Gjini, E.; Liao, X.; Chau, N.G.; Haddad, R.I.; Severgnini, M.; Hammerman, P.; El-Naggar, A.; Freeman, G.J.; Hodi, F.S.; et al. Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating Lymphocytes. Cancer Immunol. Res. 2016, 4, 679–687. [Google Scholar] [CrossRef] [PubMed]
  39. Michaelides, I.; Kunzel, J.; Ettl, T.; Beckhove, P.; Bohr, C.; Brochhausen, C.; Mamilos, A. Adenoid cystic carcinoma of the salivary glands: A pilot study of potential therapeutic targets and characterization of the immunological tumor environment and angiogenesis. Eur. Arch. Otorhinolaryngol. 2023, 280, 2937–2944. [Google Scholar] [CrossRef] [PubMed]
  40. Chen, W.; Fung, A.S.; McIntyre, J.B.; Simpson, R.; Afzal, A.R.; Hao, D.; Lau, H. Assessment of Tumour Infiltrating Lymphocytes And Pd-l1 Expression in Adenoid Cystic Carcinoma of the Salivary Gland. Clin. Investig. Med. 2021, 44, E38–E41. [Google Scholar] [CrossRef]
  41. Dou, S.; Li, R.; He, N.; Zhang, M.; Jiang, W.; Ye, L.; Yang, Y.; Zhao, G.; Yang, Y.; Li, J.; et al. The Immune Landscape of Chinese Head and Neck Adenoid Cystic Carcinoma and Clinical Implication. Front. Immunol. 2021, 12, 618367. [Google Scholar] [CrossRef]
  42. Arolt, C.; Meyer, M.; Ruesseler, V.; Nachtsheim, L.; Wuerdemann, N.; Dreyer, T.; Gattenlohner, S.; Wittekindt, C.; Buettner, R.; Quaas, A.; et al. Lymphocyte activation gene 3 (LAG3) protein expression on tumor-infiltrating lymphocytes in aggressive and TP53-mutated salivary gland carcinomas. Cancer Immunol. Immunother. 2020, 69, 1363–1373. [Google Scholar] [CrossRef]
  43. Persson, M.; Andrén, Y.; Mark, J.; Horlings, H.M.; Persson, F.; Stenman, G. Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proc. Natl. Acad. Sci. USA 2009, 106, 18740–18744. [Google Scholar] [CrossRef]
  44. Ho, A.S.; Kannan, K.; Roy, D.M.; Morris, L.G.; Ganly, I.; Katabi, N.; Ramaswami, D.; Walsh, L.A.; Eng, S.; Huse, J.T.; et al. The mutational landscape of adenoid cystic carcinoma. Nat. Genet. 2013, 45, 791–798. [Google Scholar] [CrossRef] [PubMed]
  45. Ho, A.S.; Ochoa, A.; Jayakumaran, G.; Zehir, A.; Valero Mayor, C.; Tepe, J.; Makarov, V.; Dalin, M.G.; He, J.; Bailey, M.; et al. Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma. J. Clin. Investig. 2019, 129, 4276–4289. [Google Scholar] [CrossRef] [PubMed]
  46. Sahara, S.; Herzog, A.E.; Nör, J.E. Systemic therapies for salivary gland adenoid cystic carcinoma. Am. J. Cancer Res. 2021, 11, 4092–4110. [Google Scholar] [PubMed]
  47. Agulnik, M.; Cohen, E.W.E.; Cohen, R.B.; Chen, E.X.; Vokes, E.E.; Hotte, S.J.; Winquist, E.; Laurie, S.; Hayes, D.N.; Dancey, J.E.; et al. Phase II Study of Lapatinib in Recurrent or Metastatic Epidermal Growth Factor Receptor and/or erbB2 Expressing Adenoid Cystic Carcinoma and Non–Adenoid Cystic Carcinoma Malignant Tumors of the Salivary Glands. J. Clin. Oncol. 2007, 25, 3978–3984. [Google Scholar] [CrossRef]
  48. Keam, B.; Kim, S.B.; Shin, S.H.; Cho, B.C.; Lee, K.W.; Kim, M.K.; Yun, H.J.; Lee, S.H.; Yoon, D.H.; Bang, Y.J. Phase 2 study of dovitinib in patients with metastatic or unresectable adenoid cystic carcinoma. Cancer 2015, 121, 2612–2617. [Google Scholar] [CrossRef] [PubMed]
  49. Dillon, P.M.; Petroni, G.R.; Horton, B.J.; Moskaluk, C.A.; Fracasso, P.M.; Douvas, M.G.; Varhegyi, N.; Zaja-Milatovic, S.; Thomas, C.Y. A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma. Clin. Cancer Res. 2017, 23, 4138–4145. [Google Scholar] [CrossRef]
  50. Ho, A.L.; Sherman, E.J.; Baxi, S.S.; Haque, S.; Ni, A.; Antonescu, C.R.; Katabi, N.; Morris, L.G.; Chan, T.A.-T.; Pfister, D.G. Phase II study of regorafenib in progressive, recurrent/metastatic adenoid cystic carcinoma. J. Clin. Oncol. 2016, 34, 6096. [Google Scholar] [CrossRef]
  51. Tchekmedyian, V.; Sherman, E.J.; Dunn, L.; Tran, C.; Baxi, S.; Katabi, N.; Antonescu, C.R.; Ostrovnaya, I.; Haque, S.S.; Pfister, D.G.; et al. Phase II Study of Lenvatinib in Patients with Progressive, Recurrent or Metastatic Adenoid Cystic Carcinoma. J. Clin. Oncol. 2019, 37, 1529–1537. [Google Scholar] [CrossRef]
  52. Tan, H.Y.; Wang, N.; Lam, W.; Guo, W.; Feng, Y.; Cheng, Y.C. Targeting tumour microenvironment by tyrosine kinase inhibitor. Mol. Cancer 2018, 17, 43. [Google Scholar] [CrossRef]
  53. Yang, W.; Lee, K.W.; Srivastava, R.M.; Kuo, F.; Krishna, C.; Chowell, D.; Makarov, V.; Hoen, D.; Dalin, M.G.; Wexler, L.; et al. Immunogenic neoantigens derived from gene fusions stimulate T cell responses. Nat. Med. 2019, 25, 767–775. [Google Scholar] [CrossRef]
  54. Patel, S.P.; Kurzrock, R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol. Cancer Ther. 2015, 14, 847–856. [Google Scholar] [CrossRef]
  55. Mukaigawa, T.; Hayashi, R.; Hashimoto, K.; Ugumori, T.; Hato, N.; Fujii, S. Programmed death ligand-1 expression is associated with poor disease free survival in salivary gland carcinomas. J. Surg. Oncol. 2016, 114, 36–43. [Google Scholar] [CrossRef] [PubMed]
  56. Haderlein, M.; Scherl, C.; Semrau, S.; Lettmaier, S.; Hecht, M.; Erber, R.; Iro, H.; Fietkau, R.; Agaimy, A. Impact of postoperative radiotherapy and HER2/new overexpression in salivary duct carcinoma: A monocentric clinicopathologic analysis. Strahlenther. Onkol. 2017, 193, 961–970. [Google Scholar] [CrossRef] [PubMed]
  57. Chang, H.; Kim, J.S.; Choi, Y.J.; Cho, J.G.; Woo, J.S.; Kim, A.; Kim, J.S.; Kang, E.J. Overexpression of PD-L2 is associated with shorter relapse-free survival in patients with malignant salivary gland tumors. OncoTargets Ther. 2017, 10, 2983–2992. [Google Scholar] [CrossRef] [PubMed]
  58. Harada, K.; Ferdous, T.; Ueyama, Y. PD-L1 expression in malignant salivary gland tumors. BMC Cancer 2018, 18, 156. [Google Scholar] [CrossRef] [PubMed]
  59. Szewczyk, M.; Marszalek, A.; Sygut, J.; Golusinski, P.; Golusinski, W. Prognostic markers in salivary gland cancer and their impact on survival. Head Neck 2019, 41, 3338–3347. [Google Scholar] [CrossRef]
  60. Nakano, T.; Takizawa, K.; Uezato, A.; Taguchi, K.; Toh, S.; Masuda, M. Prognostic value of programed death ligand-1 and ligand-2 co-expression in salivary gland carcinomas. Oral Oncol. 2019, 90, 30–37. [Google Scholar] [CrossRef]
  61. Vital, D.; Ikenberg, K.; Moch, H.; Rossle, M.; Huber, G.F. The expression of PD-L1 in salivary gland carcinomas. Sci. Rep. 2019, 9, 12724. [Google Scholar] [CrossRef]
  62. Hamza, A.; Roberts, D.; Su, S.; Weber, R.S.; Bell, D.; Ferrarotto, R. PD-L1 expression by immunohistochemistry in salivary duct carcinoma. Ann. Diagn. Pathol. 2019, 40, 49–52. [Google Scholar] [CrossRef]
  63. Gargano, S.M.; Senarathne, W.; Feldman, R.; Florento, E.; Stafford, P.; Swensen, J.; Vranic, S.; Gatalica, Z. Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling. Cancer Med. 2019, 8, 7322–7329. [Google Scholar] [CrossRef]
  64. Kesar, N.; Winkelmann, R.; Oppermann, J.; Ghanaati, S.; Martin, D.; Neumayer, T.; Balster, S.; Rodel, C.; Rodel, F.; von der Grun, J.; et al. Prognostic impact of CD8-positive tumour-infiltrating lymphocytes and PD-L1 expression in salivary gland cancer. Oral Oncol. 2020, 111, 104931. [Google Scholar] [CrossRef]
  65. Witte, H.M.; Gebauer, N.; Lappohn, D.; Umathum, V.G.; Riecke, A.; Arndt, A.; Steinestel, K. Prognostic Impact of PD-L1 Expression in Malignant Salivary Gland Tumors as Assessed by Established Scoring Criteria: Tumor Proportion Score (TPS), Combined Positivity Score (CPS), and Immune Cell (IC) Infiltrate. Cancers 2020, 12, 873. [Google Scholar] [CrossRef]
  66. Higashino, M.; Kawata, R.; Nishikawa, S.; Terada, T.; Haginomori, S.I.; Kurisu, Y.; Hirose, Y. Programmed death ligand-1 expression is associated with stage and histological grade of parotid carcinoma. Acta Otolaryngol. 2020, 140, 175–180. [Google Scholar] [CrossRef]
  67. Chatzopoulos, K.; Collins, A.R.; Sotiriou, S.; Keeney, M.G.; Visscher, D.W.; Rivera, M.; Schembri-Wismayer, D.J.; Lewis, J.E.; Greipp, P.T.; Sukov, W.R.; et al. Increased ERBB2 Gene Copy Numbers Reveal a Subset of Salivary Duct Carcinomas with High Densities of Tumor Infiltrating Lymphocytes and PD-L1 Expression. Head Neck Pathol. 2020, 14, 951–965. [Google Scholar] [CrossRef] [PubMed]
  68. Guazzo, E.; Cooper, C.; Wilkinson, L.; Feng, S.; King, B.; Simpson, F.; Porceddu, S.; Panizza, B.; Coward, J.I.G. Therapeutic implications of immune-profiling and EGFR expression in salivary gland carcinoma. Head Neck 2021, 43, 768–777. [Google Scholar] [CrossRef] [PubMed]
  69. Sato, F.; Ono, T.; Kawahara, A.; Matsuo, K.; Kondo, R.; Sato, K.; Akiba, J.; Kawaguchi, T.; Kakuma, T.; Chitose, S.I.; et al. Prognostic Value of Tumor Proportion Score in Salivary Gland Carcinoma. Laryngoscope 2021, 131, E1481–E1488. [Google Scholar] [CrossRef] [PubMed]
  70. Schvartsman, G.; Bell, D.; Rubin, M.L.; Tetzlaff, M.; Hanna, E.; Lee, J.J.; Weber, R.; Phan, J.; Glisson, B.S.; Ferrarotto, R. The tumor immune contexture of salivary duct carcinoma. Head Neck 2021, 43, 1213–1219. [Google Scholar] [CrossRef]
  71. Fang, Q.; Wu, Y.; Du, W.; Zhang, X.; Chen, D. Incidence and Prognostic Significance of PD-L1 Expression in High-Grade Salivary Gland Carcinoma. Front. Oncol. 2021, 11, 701181. [Google Scholar] [CrossRef] [PubMed]
  72. Vos, J.L.; Burman, B.; Jain, S.; Fitzgerald, C.W.R.; Sherman, E.J.; Dunn, L.A.; Fetten, J.V.; Michel, L.S.; Kriplani, A.; Ng, K.K.; et al. Nivolumab plus ipilimumab in advanced salivary gland cancer: A phase 2 trial. Nat. Med. 2023, 29, 3077–3089. [Google Scholar] [CrossRef] [PubMed]
  73. Bou Zerdan, M.; Kumar, P.A.; Zaccarini, D.; Ross, J.; Huang, R.; Sivapiragasam, A. Molecular Targets in Salivary Gland Cancers: A Comprehensive Genomic Analysis of 118 Mucoepidermoid Carcinoma Tumors. Biomedicines 2023, 11, 519. [Google Scholar] [CrossRef]
  74. Wu, L.; Jiang, C.; Zhu, Z.; Sun, Y.; Zhang, T. Prognostic role of PD-L1 expression in patients with salivary gland carcinoma: A systematic review and meta-analysis. PLoS ONE 2022, 17, e0272080. [Google Scholar] [CrossRef]
  75. Wang, Y.; Du, J.; Gao, Z.; Sun, H.; Mei, M.; Wang, Y.; Ren, Y.; Zhou, X. Evolving landscape of PD-L2: Bring new light to checkpoint immunotherapy. Br. J. Cancer 2022, 128, 1196–1207. [Google Scholar] [CrossRef]
  76. Yearley, J.H.; Gibson, C.; Yu, N.; Moon, C.; Murphy, E.; Juco, J.; Lunceford, J.; Cheng, J.; Chow, L.Q.M.; Seiwert, T.Y.; et al. PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. Clin. Cancer Res. 2017, 23, 3158–3167. [Google Scholar] [CrossRef]
  77. Wang, A.; Chu, H.; Jin, Z.; Jia, Q.; Zhu, B. Programmed Cell Death Protein Ligand 2 Is a Potential Biomarker That Predicts the Efficacy of Immunotherapy. Dis. Markers 2021, 2021, 9453692. [Google Scholar] [CrossRef]
  78. Fayette, J.; Even, C.; Digue, L.; Geoffrois, L.; Rolland, F.; Cupissol, D.; Guigay, J.; Tourneau, C.L.; Dillies, A.-F.; Zanetta, S.; et al. NISCAHN: A phase II, multicenter nonrandomized trial aiming at evaluating nivolumab (N) in two cohorts of patients (pts) with recurrent/metastatic (R/M) salivary gland carcinoma of the head and neck (SGCHN), on behalf of the Unicancer Head & Neck Group. J. Clin. Oncol. 2019, 37, 6083. [Google Scholar] [CrossRef]
  79. Cohen, R.B.; Delord, J.P.; Doi, T.; Piha-Paul, S.A.; Liu, S.V.; Gilbert, J.; Algazi, A.P.; Damian, S.; Hong, R.L.; Le Tourneau, C.; et al. Pembrolizumab for the Treatment of Advanced Salivary Gland Carcinoma: Findings of the Phase 1b KEYNOTE-028 Study. Am. J. Clin. Oncol. 2018, 41, 1083–1088. [Google Scholar] [CrossRef]
  80. Niwa, K.; Kawakita, D.; Nagao, T.; Takahashi, H.; Saotome, T.; Okazaki, M.; Yamazaki, K.; Okamoto, I.; Hirai, H.; Saigusa, N.; et al. Multicentre, retrospective study of the efficacy and safety of nivolumab for recurrent and metastatic salivary gland carcinoma. Sci. Rep. 2020, 10, 16988. [Google Scholar] [CrossRef] [PubMed]
  81. Rodriguez, C.P.; Wu, Q.V.; Voutsinas, J.; Fromm, J.R.; Jiang, X.; Pillarisetty, V.G.; Lee, S.M.; Santana-Davila, R.; Goulart, B.; Baik, C.S.; et al. A Phase II Trial of Pembrolizumab and Vorinostat in Recurrent Metastatic Head and Neck Squamous Cell Carcinomas and Salivary Gland Cancer. Clin. Cancer Res. 2020, 26, 837–845. [Google Scholar] [CrossRef]
  82. Hanai, N.; Shimizu, Y.; Kariya, S.; Yasumatsu, R.; Yokota, T.; Fujii, T.; Tsukahara, K.; Yoshida, M.; Hanyu, K.; Ueda, T.; et al. Effectiveness and safety of nivolumab in patients with head and neck cancer in Japanese real-world clinical practice: A multicenter retrospective clinical study. Int. J. Clin. Oncol. 2021, 26, 494–506. [Google Scholar] [CrossRef]
  83. Even, C.; Delord, J.P.; Price, K.A.; Nakagawa, K.; Oh, D.Y.; Burge, M.; Chung, H.C.; Doi, T.; Fakih, M.; Takahashi, S.; et al. Evaluation of pembrolizumab monotherapy in patients with previously treated advanced salivary gland carcinoma in the phase 2 KEYNOTE-158 study. Eur. J. Cancer 2022, 171, 259–268. [Google Scholar] [CrossRef]
  84. Rodriguez, C.P.; Wu, V.; Ng, K.; Voutsinas, J.M.; Dumenigo-Jimenez, A.; Fromm, J.R.; Martins, R.G.; Eaton, K.D.; Santana-Davila, R.; Baik, C.S.; et al. Dual PD1 and CTLA4 immune checkpoint blockade and hypofractionated radiation in patients with salivary gland cancers. J. Clin. Oncol. 2023, 41, 6011. [Google Scholar] [CrossRef]
  85. Mohamadpour, M.; Sherman, E.J.; Kriplani, A.; Fetten, J.V.; Dunn, L.; Michel, L.S.; Hung, K.W.; Baxi, S.S.; McDonald, E.; Conybeare, R.; et al. A phase II study of lenvatinib plus pembrolizumab in patients with progressive, recurrent/metastatic adenoid cystic carcinoma. J. Clin. Oncol. 2023, 41, 6048. [Google Scholar] [CrossRef]
  86. Patel, S.P.; Othus, M.; Chae, Y.K.; Giles, F.J.; Hansel, D.E.; Singh, P.P.; Fontaine, A.; Shah, M.H.; Kasi, A.; Baghdadi, T.A.; et al. A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors. Clin. Cancer Res. 2020, 26, 2290–2296. [Google Scholar] [CrossRef]
  87. Fushimi, C.; Tada, Y.; Takahashi, H.; Nagao, T.; Ojiri, H.; Masubuchi, T.; Matsuki, T.; Miura, K.; Kawakita, D.; Hirai, H.; et al. A prospective phase II study of combined androgen blockade in patients with androgen receptor-positive metastatic or locally advanced unresectable salivary gland carcinoma. Ann. Oncol. 2018, 29, 979–984. [Google Scholar] [CrossRef]
  88. Ho, A.L.; Foster, N.R.; Zoroufy, A.J.; Campbell, J.D.; Worden, F.; Price, K.; Adkins, D.; Bowles, D.W.; Kang, H.; Burtness, B.; et al. Phase II Study of Enzalutamide for Patients with Androgen Receptor-Positive Salivary Gland Cancers (Alliance A091404). J. Clin. Oncol. 2022, 40, 4240–4249. [Google Scholar] [CrossRef]
  89. Locati, L.D.; Cavalieri, S.; Bergamini, C.; Resteghini, C.; Colombo, E.; Calareso, G.; Mariani, L.; Quattrone, P.; Alfieri, S.; Bossi, P.; et al. Abiraterone Acetate in Patients with Castration-Resistant, Androgen Receptor–Expressing Salivary Gland Cancer: A Phase II Trial. J. Clin. Oncol. 2021, 39, 4061–4068. [Google Scholar] [CrossRef] [PubMed]
  90. Patel, M.; Fujioka, N.; Pease, D.F.; Feldman, L.E.; Worden, F.P.; Laux, D.E.; Boumber, Y.; Mehra, R.; Racila, E.; Cao, Q.; et al. BTCRC-HN17-111, A phase 2 trial of ADT (goserelin) in combination with pembrolizumab for patients with advanced salivary gland tumors expressing androgen receptor (AR). J. Clin. Oncol. 2022, 40, e18091. [Google Scholar] [CrossRef]
  91. Gavrielatou, N.; Doumas, S.; Economopoulou, P.; Foukas, P.G.; Psyrri, A. Biomarkers for immunotherapy response in head and neck cancer. Cancer Treat. Rev. 2020, 84, 101977. [Google Scholar] [CrossRef]
  92. Ross, J.S.; Gay, L.M.; Wang, K.; Vergilio, J.A.; Suh, J.; Ramkissoon, S.; Somerset, H.; Johnson, J.M.; Russell, J.; Ali, S.; et al. Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies. Ann. Oncol. 2017, 28, 2539–2546. [Google Scholar] [CrossRef]
  93. Kumai, T.; Yamaki, H.; Kono, M.; Hayashi, R.; Wakisaka, R.; Komatsuda, H. Antitumor Peptide-Based Vaccine in the Limelight. Vaccines 2022, 10, 70. [Google Scholar] [CrossRef]
  94. Imamura, Y.; Kiyota, N.; Tahara, M.; Hanai, N.; Asakage, T.; Matsuura, K.; Ota, I.; Saito, Y.; Sano, D.; Kodaira, T.; et al. Systemic therapy for salivary gland malignancy: Current status and future perspectives. Jpn. J. Clin. Oncol. 2022, 52, 293–302. [Google Scholar] [CrossRef] [PubMed]
  95. Kumai, T.; Oikawa, K.; Aoki, N.; Kimura, S.; Harabuchi, Y.; Kobayashi, H. Assessment of the change in cetuximab-induced antibody-dependent cellular cytotoxicity activity of natural killer cells by steroid. Head Neck 2016, 38, 410–416. [Google Scholar] [CrossRef]
  96. Takahashi, H.; Tada, Y.; Saotome, T.; Akazawa, K.; Ojiri, H.; Fushimi, C.; Masubuchi, T.; Matsuki, T.; Tani, K.; Osamura, R.Y.; et al. Phase II Trial of Trastuzumab and Docetaxel in Patients with Human Epidermal Growth Factor Receptor 2-Positive Salivary Duct Carcinoma. J. Clin. Oncol. 2019, 37, 125–134. [Google Scholar] [CrossRef]
  97. Kinoshita, I.; Kano, S.; Shimizu, Y.; Kiyota, N.; Tada, Y.; Ijichi, K.; Yamazaki, T.; Homma, A.; Ito, Y.M.; Ono, K.; et al. Abstract CT137: Phase II study of trastuzumab and docetaxel therapy in patients with HER2-positive recurrent and/or metastatic salivary gland carcinoma. Cancer Res. 2019, 79, CT137. [Google Scholar] [CrossRef]
  98. Kawakita, D.; Nagao, T.; Takahashi, H.; Kano, S.; Honma, Y.; Hirai, H.; Saigusa, N.; Akazawa, K.; Tani, K.; Ojiri, H.; et al. Survival benefit of HER2-targeted or androgen deprivation therapy in salivary duct carcinoma. Ther. Adv. Med. Oncol. 2022, 14, 17588359221119538. [Google Scholar] [CrossRef]
  99. Jakob, J.A.; Kies, M.S.; Glisson, B.S.; Kupferman, M.E.; Liu, D.D.; Lee, J.J.; El-Naggar, A.K.; Gonzalez-Angulo, A.M.; Blumenschein, G.R., Jr. Phase II study of gefitinib in patients with advanced salivary gland cancers. Head Neck 2015, 37, 644–649. [Google Scholar] [CrossRef]
  100. Locati, L.D.; Bossi, P.; Perrone, F.; Potepan, P.; Crippa, F.; Mariani, L.; Casieri, P.; Orsenigo, M.; Losa, M.; Bergamini, C.; et al. Cetuximab in recurrent and/or metastatic salivary gland carcinomas: A phase II study. Oral Oncol. 2009, 45, 574–578. [Google Scholar] [CrossRef] [PubMed]
  101. Nakano, T.; Yasumatsu, R.; Hashimoto, K.; Kuga, R.; Hongo, T.; Yamamoto, H.; Matsuo, M.; Wakasaki, T.; Jiromaru, R.; Manako, T.; et al. Retrospective Study of Cisplatin/Carboplatin, 5-Fluorouracil Plus Cetuximab (EXTREME) for Advanced-stage Salivary Gland Cancer. Vivo 2022, 36, 979–984. [Google Scholar] [CrossRef]
  102. Sato, R.; Yuasa, R.; Kumai, T.; Wakisaka, R.; Komatsuda, H.; Kono, M.; Yamaki, H.; Ishida, Y.; Wada, T.; Takahara, M.; et al. Efficacy of Cetuximab Combined with Paclitaxel in Patients with Recurrent Salivary Gland Carcinoma: A Retrospective Observational Study. ORL J. Otorhinolaryngol. Relat. Spec. 2023, 86, 41–49. [Google Scholar] [CrossRef]
  103. Makita, Y.; Kunii, N.; Sakurai, D.; Ihara, F.; Motohashi, S.; Suzuki, A.; Nakayama, T.; Okamoto, Y. Activated iNKT cells enhance the anti-tumor effect of antigen specific CD8 T cells on mesothelin-expressing salivary gland cancer. BMC Cancer 2018, 18, 1254. [Google Scholar] [CrossRef]
  104. Secondino, S.; Canino, C.; Alaimo, D.; Muzzana, M.; Galli, G.; Borgetto, S.; Basso, S.; Bagnarino, J.; Pulvirenti, C.; Comoli, P.; et al. Clinical Trials of Cellular Therapies in Solid Tumors. Cancers 2023, 15, 3667. [Google Scholar] [CrossRef]
  105. He, M.; Zhang, D.; Cao, Y.; Chi, C.; Zeng, Z.; Yang, X.; Yang, G.; Sharma, K.; Hu, K.; Enikeev, M. Chimeric antigen receptor-modified T cells therapy in prostate cancer: A comprehensive review on the current state and prospects. Heliyon 2023, 9, e19147. [Google Scholar] [CrossRef]
  106. Narayan, V.; Barber-Rotenberg, J.S.; Jung, I.Y.; Lacey, S.F.; Rech, A.J.; Davis, M.M.; Hwang, W.T.; Lal, P.; Carpenter, E.L.; Maude, S.L.; et al. PSMA-targeting TGFbeta-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: A phase 1 trial. Nat. Med. 2022, 28, 724–734. [Google Scholar] [CrossRef]
  107. Klein Nulent, T.J.W.; Valstar, M.H.; Smit, L.A.; Smeele, L.E.; Zuithoff, N.P.A.; de Keizer, B.; de Bree, R.; van Es, R.J.J.; Willems, S.M. Prostate-specific membrane antigen (PSMA) expression in adenoid cystic carcinoma of the head and neck. BMC Cancer 2020, 20, 519. [Google Scholar] [CrossRef]
  108. van Boxtel, W.; Lutje, S.; van Engen-van Grunsven, I.C.H.; Verhaegh, G.W.; Schalken, J.A.; Jonker, M.A.; Nagarajah, J.; Gotthardt, M.; van Herpen, C.M.L. 68Ga-PSMA-HBED-CC PET/CT imaging for adenoid cystic carcinoma and salivary duct carcinoma: A phase 2 imaging study. Theranostics 2020, 10, 2273–2283. [Google Scholar] [CrossRef]
  109. Wang, G.; Zhou, M.; Zang, J.; Jiang, Y.; Chen, X.; Zhu, Z.; Chen, X. A pilot study of 68Ga-PSMA-617 PET/CT imaging and (177)Lu-EB-PSMA-617 radioligand therapy in patients with adenoid cystic carcinoma. EJNMMI Res 2022, 12, 52. [Google Scholar] [CrossRef]
  110. Klein Nulent, T.J.W.; van Es, R.J.J.; Willems, S.M.; Braat, A.; Devriese, L.A.; de Bree, R.; de Keizer, B. First experiences with (177)Lu-PSMA-617 therapy for recurrent or metastatic salivary gland cancer. EJNMMI Res. 2021, 11, 126. [Google Scholar] [CrossRef]
  111. Ahmed, N.; Brawley, V.; Hegde, M.; Bielamowicz, K.; Kalra, M.; Landi, D.; Robertson, C.; Gray, T.L.; Diouf, O.; Wakefield, A.; et al. HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial. JAMA Oncol. 2017, 3, 1094–1101. [Google Scholar] [CrossRef]
  112. Hein, K.Z.; Yao, S.; Fu, S. Wilms’ Tumor 1 (WT1): The Vaccine for Cancer. J. Immunother. Precis. Oncol. 2020, 3, 165–171. [Google Scholar] [CrossRef] [PubMed]
  113. Shirakata, T.; Oka, Y.; Nishida, S.; Hosen, N.; Tsuboi, A.; Oji, Y.; Murao, A.; Tanaka, H.; Nakatsuka, S.; Inohara, H.; et al. WT1 peptide therapy for a patient with chemotherapy-resistant salivary gland cancer. Anticancer Res. 2012, 32, 1081–1085. [Google Scholar] [PubMed]
  114. Sasabe, E.; Hamada, F.; Iiyama, T.; Udaka, K.; Sugiyama, H.; Yamamoto, T. Wilm’s tumor gene WT1 peptide immunotherapy for pulmonary metastasis from adenoid cystic carcinoma of the salivary gland. Oral Oncol. 2011, 47, 77–78. [Google Scholar] [CrossRef]
  115. Ho, S.Y.; Chang, C.M.; Liao, H.N.; Chou, W.H.; Guo, C.L.; Yen, Y.; Nakamura, Y.; Chang, W.C. Current Trends in Neoantigen-Based Cancer Vaccines. Pharmaceuticals 2023, 16, 392. [Google Scholar] [CrossRef] [PubMed]
  116. Song, Q.; Yang, B.; Sheng, W.; Zhou, Z.; Zhang, T.; Qin, B.; Ji, L.; Li, P.; Wang, D.; Zhang, X.; et al. Safety and efficacy of mutant neoantigen-specific T-cell treatment combined anti-PD-1 therapy in stage IV solid tumors. Immunotherapy 2022, 14, 553–565. [Google Scholar] [CrossRef] [PubMed]
  117. Ott, P.A.; Hu, Z.; Keskin, D.B.; Shukla, S.A.; Sun, J.; Bozym, D.J.; Zhang, W.; Luoma, A.; Giobbie-Hurder, A.; Peter, L.; et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 2017, 547, 217–221. [Google Scholar] [CrossRef]
  118. Chen, Z.; Zhang, S.; Han, N.; Jiang, J.; Xu, Y.; Ma, D.; Lu, L.; Guo, X.; Qiu, M.; Huang, Q.; et al. A Neoantigen-Based Peptide Vaccine for Patients with Advanced Pancreatic Cancer Refractory to Standard Treatment. Front. Immunol. 2021, 12, 691605. [Google Scholar] [CrossRef]
  119. Ichimiya, S.; Fujimura, A.; Masuda, M.; Masuda, S.; Yasumatsu, R.; Umebayashi, M.; Tanaka, H.; Koya, N.; Nakagawa, S.; Yew, P.Y.; et al. Contribution of pre-existing neoantigen-specific T cells to a durable complete response after tumor-pulsed dendritic cell vaccine plus nivolumab therapy in a patient with metastatic salivary duct carcinoma. Immunol. Investig. 2022, 51, 1498–1514. [Google Scholar] [CrossRef]
  120. Zhu, J.; Fang, P.; Wang, C.; Gu, M.; Pan, B.; Guo, W.; Yang, X.; Wang, B. The immunomodulatory activity of lenvatinib prompts the survival of patients with advanced hepatocellular carcinoma. Cancer Med. 2021, 10, 7977–7987. [Google Scholar] [CrossRef]
  121. Kato, Y.; Tabata, K.; Kimura, T.; Yachie-Kinoshita, A.; Ozawa, Y.; Yamada, K.; Ito, J.; Tachino, S.; Hori, Y.; Matsuki, M.; et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS ONE 2019, 14, e0212513. [Google Scholar] [CrossRef]
  122. Nishimura, H.; Jin, D.; Kinoshita, I.; Taniuchi, M.; Higashino, M.; Terada, T.; Takai, S.; Kawata, R. Increased Chymase-Positive Mast Cells in High-Grade Mucoepidermoid Carcinoma of the Parotid Gland. Int. J. Mol. Sci. 2023, 24, 8267. [Google Scholar] [CrossRef]
  123. Xiao, C.; Pan, Y.; Zeng, X.; Wang, L.; Li, Z.; Yan, S.; Wang, H. Downregulation of hypoxia-inducible factor-1alpha inhibits growth, invasion, and angiogenesis of human salivary adenoid cystic carcinoma cells under hypoxia. Oncol. Rep. 2018, 40, 1675–1683. [Google Scholar] [CrossRef] [PubMed]
  124. Colton, M.; Cheadle, E.J.; Honeychurch, J.; Illidge, T.M. Reprogramming the tumour microenvironment by radiotherapy: Implications for radiotherapy and immunotherapy combinations. Radiat. Oncol. 2020, 15, 254. [Google Scholar] [CrossRef] [PubMed]
  125. Li, D.; Pang, X.; Zhu, X.; Shanzhou, Q.; Wen, G.; Ma, D. Low-dose radiotherapy combined with immunotherapy for suboral adenoid cystic carcinoma with bilateral lung metastasis: A case report and literature review. Oncol. Lett. 2022, 24, 279. [Google Scholar] [PubMed]
  126. Jeske, S.S.; Weissinger, S.E.; Veit, J.A.; Brunner, C.; Huber, U.; Theodoraki, M.N.; Hoffmann, T.K.; Schuler, P.J.; Doescher, J. Treatment-induced changes of lymphocyte subsets in patients with adenoid cystic carcinoma of the head and neck. Eur. Arch. Otorhinolaryngol. 2019, 276, 1465–1473. [Google Scholar] [CrossRef] [PubMed]
  127. Franks, S.E.; Santiago-Sanchez, G.S.; Fabian, K.P.; Solocinski, K.; Chariou, P.L.; Hamilton, D.H.; Kowalczyk, J.T.; Padget, M.R.; Gameiro, S.R.; Schlom, J.; et al. Exploiting docetaxel-induced tumor cell necrosis with tumor targeted delivery of IL-12. Cancer Immunol. Immunother. 2023, 72, 2783–2797. [Google Scholar] [CrossRef] [PubMed]
  128. Su, X.; Xu, W.; Guan, R.; Wang, Y.; Wu, J.; Zhai, L.; Chen, G.; Hu, S. Adjuvant effect of docetaxel on HPV16 L2E6E7 fusion protein vaccine in a mouse model. Int. Immunopharmacol. 2016, 38, 16–25. [Google Scholar] [CrossRef] [PubMed]
  129. Harrop, R.; Chu, F.; Gabrail, N.; Srinivas, S.; Blount, D.; Ferrari, A. Vaccination of castration-resistant prostate cancer patients with TroVax (MVA-5T4) in combination with docetaxel: A randomized phase II trial. Cancer Immunol. Immunother. 2013, 62, 1511–1520. [Google Scholar] [CrossRef]
  130. Kumai, T.; Lee, S.; Cho, H.I.; Sultan, H.; Kobayashi, H.; Harabuchi, Y.; Celis, E. Optimization of Peptide Vaccines to Induce Robust Antitumor CD4 T-cell Responses. Cancer Immunol. Res. 2017, 5, 72–83. [Google Scholar] [CrossRef]
Cancers 16 01205 g001
Figure 1. Comparison of tumor microenvironment between (a) mucoepidermoid carcinoma and (b) adenoid cystic carcinoma. Infiltration of immune cells and expression of immune checkpoint molecules are relatively high in mucoepidermoid carcinomas. Immune regulatory cells, including MDSC, infiltrate the tumor microenvironment of adenoid cystic carcinoma. MDSC, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages; VEGF, vascular endothelial growth factor.
Figure 1. Comparison of tumor microenvironment between (a) mucoepidermoid carcinoma and (b) adenoid cystic carcinoma. Infiltration of immune cells and expression of immune checkpoint molecules are relatively high in mucoepidermoid carcinomas. Immune regulatory cells, including MDSC, infiltrate the tumor microenvironment of adenoid cystic carcinoma. MDSC, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages; VEGF, vascular endothelial growth factor.
Cancers 16 01205 g001
Table 1. Expression rates of PD-L1 in major histological types of salivary gland cancers.
Table 1. Expression rates of PD-L1 in major histological types of salivary gland cancers.
No.AuthorPD-L1 ScoringCut OffSDCAdenocarcinoma-NOSMECAdCCACCOthersTotal
1Mukaigawa et al., 2016 [55]TC≥1%15/31 (48%)4/11 (36%)3/34 (9%)1/53 (2%)0/18 (0%)9/28 (32%)50/219 (23%)
IC≥1%9/31 (29%)2/11 (18%)2/34 (6%)0/53 (0%)1/18 (6%)6/28 (21%)28/219 (13%)
2Sridharan et al., 2016 [38]TC≥5% 0/21 (0%) 0/21 (0%)
3Haderlein et al., 2017 [56]CPS≥511/50 (22%) 11/50 (22%)
4Chang et al., 2017 [57]H-score≥15/11 (45%) 7/27 (26%)4/15 (27%) 16/53 (30%)
5Harada et al., 2018 [58]TC≥5% 5/9 (56%)7/11 (64%)11/25 (44%) 1/2 (50%)24/47 (51%)
6Szewczyk et al., 2019 [59]TC≥5%1/16 (6%)1/13 (8%)3/16 (19%)10/33 (30%)0/15 (0%)0/9 (0%)20/115 (17%)
IC≥5%2/16 (13%)0/13 (0%)1/16 (6%)0/33 (0%)0/15 (0%)0/9 (0%)3/115 (3%)
7Nakano et al., 2019 [60]TC≥1%4/8 (50%) 4/7 (57%)0/11 (0%) 1/4 (25%)11/32 (34%)
8Vital et al., 2019 [61]TC≥1%3/10 (30%)2/12 (17%)9/36 (25%)3/36 (8%) 7/37 (19%)28/161 (17%)
9Mosconi et al., 2019 [37]TC≥10% 0/36 (0%) 0/36 (0%)
10Hamza et al., 2019 [62]TC≥1%29/113 (26%) 29/113 (26%)
11Gargano et al., 2019 [63]TC≥1%5/28 (18%) 5/28 (18%)
12Xu et al., 2019 [31]CPS≥120/36 (56%) 15/17 (88%)35/53 (66%)
13Kesar et al., 2020 [64]TC≥5% 6/26 (23%)2/10 (20%)0/16 (0%)1/7 (14%)4/8 (50%)13/67 (19%)
14Witte et al., 2020 [65]TC≥1%1/1 (100%)12/12 (100%)11/21 (52%)16/41 (39%)13/16 (81%)3/3 (100%)61/94 (65%)
IC≥5%1/1 (100%)8/12 (66%)7/21 (33%)7/41 (17%)2/16 (13%)0/1 (0%)25/92 (27%)
CPS≥11/1 (100%)12/12 (100%)15/21 (71%)10/41 (24%)10/16 (63%)2/3 (67%)75/94 (80%)
15Higashino et al., 2020 [66]TC≥1%6/10 (60%)0/1 (0%)10/33 (30%)1/17 (6%)5/19 (26%)14/34 (41%)36/127 (28%)
16Chatzopoulos et al., 2020 [67]CPS≥113/32 (41%) 13/32 (41%)
17Guazzo et al., 2021 [68]CPS≥15/14 (36%) 2/11 (18%)0/17 (0%)0/6 (0%) 7/48 (15%)
18Sato et al., 2021 [69]TC≥1%5/8 (63%)2/4 (50%)8/20 (40%)2/13 (15%)2/7 (29%)5/10 (50%)24/62 (39%)
IC≥1%7/8 (88%)4/4 (100%)12/20 (60%)2/13 (15%)6/7 (86%) 35/62 (56%)
CPS≥17/8 (88%)4/4 (100%)12/20 (60%)3/13 (20%)6/7 (86%) 37/62 (60%)
19Schvartsman et al., 2021 [70]TC≥1%9/17 (53%) 9/17 (53%)
20Dou et al., 2021 [41]TC≥1% 17/62 (27%) 17/62 (27%)
21Chen et al., 2021 [40]TC≥1% 0/16 (0%) 0/16 (0%)
22Fang et al., 2021 [71]TC≥1%14/33 (42%)8/15 (53%)19/47 (40%) 41/95 (43%)
IC≥1%13/33 (39%)7/15 (47%)21/47(45%) 41/95 (43%)
CPS≥125/33 (76%)12/15 (80%)38/47 (81%) 75/95 (79%)
23Vos et al., 2023 [72]TC≥1%1/6 (33%) 0/2 (0%)2/25 (8%)2/4 (50%)2/10 (20%)7/47 (15%)
24Hirai et al., 2023 [28]TC≥1%32/175 (18%) 32/175 (18%)
CPS≥193/175 (53%) 93/175 (53%)
25Michaelides et al., 2023 [39]CPS≥5 0/12 (0%) 0/12 (0%)
26Zerdan et al., 2023 [73]TC≥1% 31/118 (26%) 31/118 (26%)
<Scoring methods of PD-L1> TC: the percentage of PD-L1 positive tumor cells. IC: the percentage of PD-L1 positive immune cells. CPS: the total number of positive cells, including tumor cells and surrounding immune cells (lymphocytes and macrophages), divided by the total number of tumor cells, multiplied by 100. H-score: multipling the percentage of cells with 1+, 2+ or 3+ staining by the percentage of positive cells. ACC: acinic cell carcinoma, AdCC: adenoid cystic carcinoma, CPS: combined positive score, IC: immune cells, MEC: mucoepidermoid carcinoma, NOS: not otherwise specified, PD-L1: programmed death ligand-1, SDC: salivary duct carcinoma, SGC: salivary gland cancer, TC: tumor cells.
Table 2. Clinical efficacy of immune checkpoint inhibitors in patients with salivary gland cancers.
Table 2. Clinical efficacy of immune checkpoint inhibitors in patients with salivary gland cancers.
No.AuthorNumber of CasesTypes of SGCsTreatment RegimensORR CBRMedian OS (M)Median PFS (M)
1Fayette et al., 2019 [78]98TotalNivolumab4.6%53.2%21.1-
46AdCC8.7%33.3%18.1-
52Non AdCC3.8%14.0%9.5-
2Niwa et al., 2020 [80]24AnyNivolumab4.2%12.5%--
3Hanai et al., 2021 [82]22AnyNivolumab13.6%-NR2.1
4Ueda et al., 2022 [12]12AnyNivolumab25.0%-16.2-
5Cohen et al., 2018 [79]26PD-L1 positive SGCPembrolizumab11.5%23.0%134.0
6Mahmood et al., 2020 [13]10AnyPembrolizumab0%70.0%27.26.6
10AnyPembrolizumab + RT0%50.0%NR4.5
7Even et al., 2022 [83]105TotalPembrolizumab4.0%54.1%21.1 4.0
28PD-L1 positive SGC10.7%42.8%--
77PD-L1 negative SGC2.6%58.4%--
8Sato et al., 2022 [11]12AnyNivolumab or Pembrolizumab33.3%33.3%13.54.0
9Patel et al., 2021 [54]26AdCCNivolumab + Ipilimumab4.0%-12.0-
35Non AdCC9.0%-NR-
10Vos et al., 2023 [72]32AdCCNivolumab + Ipilimumab6.3%34.4%19.34.4
32Non AdCC16.0%18.8%2.22.2
11Rodriguez et al., 2020 [81]25AnyPembrolizumab + Vorinostat16.0%72.0%14.0 6.9
12Rodriguez et al., 2023 [84]20AnyNivolumab + Ipilimumab + RT20.0%50.0%25.0 7.2
13Mohamadpour et al., 2023 [85]17AdCCPembrolizumab + Lenvatinib6.0%82.0%--
AdCC: adenoid cystic carcinoma, CBR: clinical benefit rate, ICI: Immune checkpoint inhibitor, M: months, NR: not reached, ORR: objective response rate, OS: overall survival, PD-L1: programmed death ligand-1, PFS: progression-free survival, RT: radiation therapy, SGC: salivary gland cancer.
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Sato, R.; Yamaki, H.; Komatsuda, H.; Wakisaka, R.; Inoue, T.; Kumai, T.; Takahara, M. Exploring Immunological Effects and Novel Immune Adjuvants in Immunotherapy for Salivary Gland Cancers. Cancers 2024, 16, 1205. https://doi.org/10.3390/cancers16061205

AMA Style

Sato R, Yamaki H, Komatsuda H, Wakisaka R, Inoue T, Kumai T, Takahara M. Exploring Immunological Effects and Novel Immune Adjuvants in Immunotherapy for Salivary Gland Cancers. Cancers. 2024; 16(6):1205. https://doi.org/10.3390/cancers16061205

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Sato, Ryosuke, Hidekiyo Yamaki, Hiroki Komatsuda, Risa Wakisaka, Takahiro Inoue, Takumi Kumai, and Miki Takahara. 2024. "Exploring Immunological Effects and Novel Immune Adjuvants in Immunotherapy for Salivary Gland Cancers" Cancers 16, no. 6: 1205. https://doi.org/10.3390/cancers16061205

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