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11 pages, 255 KiB

Open AccessEditorial

Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities

by Fabrizio Mattei, Carlos Alfaro and Yona Keisari

Cells 2022, 11(3), 459; https://doi.org/10.3390/cells11030459 - 28 Jan 2022

Viewed by 2963

Abstract

The gradual and more profound dissection of the molecular basis of cancer progression, carcinogenesis, and metastatic spread of cancer cells has led to more focused, effective, and targeted therapeutic approaches in the disparate types of solid and hematological tumors, particularly those with high [...] Read more.

The gradual and more profound dissection of the molecular basis of cancer progression, carcinogenesis, and metastatic spread of cancer cells has led to more focused, effective, and targeted therapeutic approaches in the disparate types of solid and hematological tumors, particularly those with high ability to metastasize distant organs [...] Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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Research

Jump to: Editorial, Review

19 pages, 4267 KiB

Open AccessArticle

Extracellular HSP90α Induces MyD88-IRAK Complex-Associated IKKα/β−NF-κB/IRF3 and JAK2/TYK2−STAT-3 Signaling in Macrophages for Tumor-Promoting M2-Polarization

by Chi-Shuan Fan, Chia-Chi Chen, Li-Li Chen, Kee Voon Chua, Hui-Chen Hung, John T. -A. Hsu and Tze-Sing Huang

Cells 2022, 11(2), 229; https://doi.org/10.3390/cells11020229 - 11 Jan 2022

Cited by 31 | Viewed by 3927

Abstract

M2-polarization and the tumoricidal to tumor-promoting transition are commonly observed with tumor-infiltrating macrophages after interplay with cancer cells or/and other stroma cells. Our previous study indicated that macrophage M2-polarization can be induced by extracellular HSP90α (eHSP90α) secreted from endothelial-to-mesenchymal transition-derived cancer-associated fibroblasts. To [...] Read more.

M2-polarization and the tumoricidal to tumor-promoting transition are commonly observed with tumor-infiltrating macrophages after interplay with cancer cells or/and other stroma cells. Our previous study indicated that macrophage M2-polarization can be induced by extracellular HSP90α (eHSP90α) secreted from endothelial-to-mesenchymal transition-derived cancer-associated fibroblasts. To extend the finding, we herein validated that eHSP90α-induced M2-polarized macrophages exhibited a tumor-promoting activity and the promoted tumor tissues had significant increases in microvascular density but decreases in CD4⁺ T-cell level. We further investigated the signaling pathways occurring in eHSP90α-stimulated macrophages. When macrophages were exposed to eHSP90α, CD91 and toll-like receptor 4 (TLR4) functioned as the receptor/co-receptor for eHSP90α binding to recruit interleukin (IL)-1 receptor-associated kinases (IRAKs) and myeloid differentiation factor 88 (MyD88), and next elicited a canonical CD91/MyD88–IRAK1/4–IκB kinase α/β (IKKα/β)–nuclear factor-κB (NF-κB)/interferon regulatory factor 3 (IRF3) signaling pathway. Despite TLR4-MyD88 complex-associated activations of IKKα/β, NF-κB and IRF3 being well-known as involved in macrophage M1-activation, our results demonstrated that the CD91-TLR4-MyD88 complex-associated IRAK1/4−IKKα/β−NF-κB/IRF3 pathway was not only directly involved in M2-associated CD163, CD204, and IL-10 gene expressions but also required for downregulation of M1 inflammatory cytokines. Additionally, Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2) were recruited onto MyD88 to induce the phosphorylation and activation of the transcription factor signal transducer and activator of transcription-3 (STAT-3). The JAK2/TYK2−STAT-3 signaling is known to associate with tumor promotion. In this study, the MyD88−JAK2/TYK2−STAT-3 pathway was demonstrated to contribute to eHSP90α-induced macrophage M2-polarization by regulating the expressions of M1- and M2-related genes, proangiogenic protein vascular endothelial growth factor, and phagocytosis-interfering factor Sec22b. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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11 pages, 1899 KiB

Open AccessArticle

Alterations in Immune Response Profile of Tumor-Draining Lymph Nodes after High-Intensity Focused Ultrasound Ablation of Breast Cancer Patients

by Xue-Qiang Zhu, Pei Lu, Zhong-Lin Xu, Qiang Zhou, Jun Zhang, Zhi-Biao Wang and Feng Wu

Cells 2021, 10(12), 3346; https://doi.org/10.3390/cells10123346 - 29 Nov 2021

Cited by 16 | Viewed by 3248

Abstract

Previous studies have revealed that high-intensity focused ultrasound (HIFU) ablation can trigger an antitumor immune response. The aim of this study was to investigate immune response in tumor-draining lymph nodes (TDLNs) after HIFU treatment. Forty-eight female patients with biopsy-confirmed breast cancer were divided [...] Read more.

Previous studies have revealed that high-intensity focused ultrasound (HIFU) ablation can trigger an antitumor immune response. The aim of this study was to investigate immune response in tumor-draining lymph nodes (TDLNs) after HIFU treatment. Forty-eight female patients with biopsy-confirmed breast cancer were divided into a control group and an HIFU group. In the control group, 25 patients underwent modified radical mastectomy, but 23 patients in the HIFU group received HIFU ablation of primary cancer, followed by the same operation. Using HE and immunohistochemical staining, the immunologic reactivity pattern and immune cell profile were assessed in paraffin-embedded axillary lymph nodes (ALNs) in all patients. The results showed that ALNs presented more evident immune reactions in the HIFU group than in the control group (100% vs. 64%). Among the ALNs, 78.3% had mixed cellular and humoral immune response, whereas 36% in the control group showed cellular immune response. The numbers of CD3⁺, CD4⁺, NK cell, and activated CTLs with Fas ligand⁺, granzyme⁺ and perforin⁺ expression were significantly higher in the ALNs in the HIFU group. It was concluded that HIFU could stimulate potent immune response and significantly increase T cell, activated CTLs and NK cell populations in the TDLNs of breast cancer. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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17 pages, 3710 KiB

Open AccessArticle

Ewing Sarcoma-Derived Extracellular Vesicles Impair Dendritic Cell Maturation and Function

by Hendrik Gassmann, Kira Schneider, Valentina Evdokimova, Peter Ruzanov, Sebastian J. Schober, Busheng Xue, Kristina von Heyking, Melanie Thiede, Guenther H. S. Richter, Michael W. Pfaffl, Elfriede Noessner, Lincoln D. Stein, Poul H. Sorensen, Stefan E. G. Burdach and Uwe Thiel

Cells 2021, 10(8), 2081; https://doi.org/10.3390/cells10082081 - 13 Aug 2021

Cited by 19 | Viewed by 4527

Abstract

Ewing sarcoma (EwS) is an aggressive pediatric cancer of bone and soft tissues characterized by scant T cell infiltration and predominance of immunosuppressive myeloid cells. Given the important roles of extracellular vesicles (EVs) in cancer-host crosstalk, we hypothesized that EVs secreted by EwS [...] Read more.

Ewing sarcoma (EwS) is an aggressive pediatric cancer of bone and soft tissues characterized by scant T cell infiltration and predominance of immunosuppressive myeloid cells. Given the important roles of extracellular vesicles (EVs) in cancer-host crosstalk, we hypothesized that EVs secreted by EwS tumors target myeloid cells and promote immunosuppressive phenotypes. Here, EVs were purified from EwS and fibroblast cell lines and exhibited characteristics of small EVs, including size (100–170 nm) and exosome markers CD63, CD81, and TSG101. Treatment of healthy donor-derived CD33⁺ and CD14⁺ myeloid cells with EwS EVs but not with fibroblast EVs induced pro-inflammatory cytokine release, including IL-6, IL-8, and TNF. Furthermore, EwS EVs impaired differentiation of these cells towards monocytic-derived dendritic cells (moDCs), as evidenced by reduced expression of co-stimulatory molecules CD80, CD86 and HLA-DR. Whole transcriptome analysis revealed activation of gene expression programs associated with immunosuppressive phenotypes and pro-inflammatory responses. Functionally, moDCs differentiated in the presence of EwS EVs inhibited CD4⁺ and CD8⁺ T cell proliferation as well as IFNγ release, while inducing secretion of IL-10 and IL-6. Therefore, EwS EVs may promote a local and systemic pro-inflammatory environment and weaken adaptive immunity by impairing the differentiation and function of antigen-presenting cells. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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20 pages, 3055 KiB

Open AccessArticle

Human Lung-Resident Macrophages Express and Are Targets of Thymic Stromal Lymphopoietin in the Tumor Microenvironment

by Mariantonia Braile, Alfonso Fiorelli, Daniela Sorriento, Rosa Maria Di Crescenzo, Maria Rosaria Galdiero, Gianni Marone, Mario Santini, Gilda Varricchi and Stefania Loffredo

Cells 2021, 10(8), 2012; https://doi.org/10.3390/cells10082012 - 6 Aug 2021

Cited by 25 | Viewed by 4054

Abstract

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine highly expressed by epithelial cells and several innate and adaptive immune cells. TSLP exerts its biological effects by binding to a heterodimeric complex composed of TSLP receptor (TSLPR) and IL-7Rα. In humans, there are two [...] Read more.

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine highly expressed by epithelial cells and several innate and adaptive immune cells. TSLP exerts its biological effects by binding to a heterodimeric complex composed of TSLP receptor (TSLPR) and IL-7Rα. In humans, there are two TSLP isoforms: the short form (sfTSLP), constitutively expressed, and the long form (lfTSLP), which is upregulated in inflammation. TSLP has been implicated in the induction and progression of several experimental and human cancers. Primary human lung macrophages (HLMs), monocyte-derived macrophages (MDMs), and peripheral blood monocytes consitutively expressed sfTSLP mRNA. Incubation of HLMs, MDMs, and monocytes with lipopolysaccharide (LPS) or IL-4, but not with IL-13, induced TSLP release from HLMs. LPS, but not IL-4 or IL-13, induced CXCL8 release from HLMs. LPS, IL-4 alone or in combination with IL-13, induced the expression of lfTSLP, but not of sfTSLP from HLMs. Preincubation of HLMs with IL-4, alone or in combination with IL-13, but not IL-13 alone, synergistically enhanced TSLP release from LPS-activated macrophages. By contrast, IL-4, alone or in combination with IL-13, inhibited LPS-induced CXCL8 release from HLMs. Immunoreactive TSLP was detected in lysates of HLMs, MDMs, and monocytes. Incubation of HLMs with TSLP induced the release of proinflammatory (TNF-α), angiogenic (VEGF-A, angiopoietin 2), and lymphangiogenic (VEGF-C) factors. TSLP, TSLPR, and IL-7Rα were expressed in intratumoral and peritumoral areas of human lung cancer. sfTSLP and lfTSLP mRNAs were differentially expressed in peritumoral and intratumoral lung cancer tissues. The TSLP system, expressed in HLMs, MDMs, and monocytes, could play a role in chronic inflammatory disorders including lung cancer. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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23 pages, 6178 KiB

Open AccessArticle

In Vitro Examinations of Cell Death Induction and the Immune Phenotype of Cancer Cells Following Radiative-Based Hyperthermia with 915 MHz in Combination with Radiotherapy

by Michael Hader, Simon Streit, Andreas Rosin, Thorsten Gerdes, Martin Wadepohl, Sander Bekeschus, Rainer Fietkau, Benjamin Frey, Eberhard Schlücker, Stephan Gekle and Udo S. Gaipl

Cells 2021, 10(6), 1436; https://doi.org/10.3390/cells10061436 - 8 Jun 2021

Cited by 10 | Viewed by 3109

Abstract

Multimodal tumor treatment settings consisting of radiotherapy and immunomodulating agents such as immune checkpoint inhibitors are more and more commonly applied in clinics. In this context, the immune phenotype of tumor cells has a major influence on the anti-tumor immune response as well [...] Read more.

Multimodal tumor treatment settings consisting of radiotherapy and immunomodulating agents such as immune checkpoint inhibitors are more and more commonly applied in clinics. In this context, the immune phenotype of tumor cells has a major influence on the anti-tumor immune response as well as the composition of the tumor microenvironment. A promising approach to further boost anti-tumor immune responses is to add hyperthermia (HT), i.e., heating the tumor tissue between 39 °C to 45 °C for 60 min. One key technique is the use of radiative hyperthermia systems. However, knowledge is limited as to how the frequency of the used radiative systems affects the immune phenotype of the treated tumor cells. By using our self-designed in vitro hyperthermia system, we compared cell death induction and expression of immune checkpoint molecules (ICM) on the tumor cell surface of murine B16 melanoma and human MDA-MB-231 and MCF-7 breast cancer cells following HT treatment with clinically relevant microwaves at 915 MHz or 2.45 GHz alone, radiotherapy (RT; 2 × 5 Gy or 5 × 2 Gy) alone or in combination (RHT). At 44 °C, HT alone was the dominant cell death inductor with inactivation rates of around 70% for B16, 45% for MDA-MB-231 and 35% for MCF-7 at 915 MHz and 80%, 60% and 50% at 2.45 GHz, respectively. Additional RT resulted in 5–15% higher levels of dead cells. The expression of ICM on tumor cells showed time-, treatment-, cell line- and frequency-dependent effects and was highest for RHT. Computer simulations of an exemplary spherical cell revealed frequency-dependent local energy absorption. The frequency of hyperthermia systems is a newly identified parameter that could also affect the immune phenotype of tumor cells and consequently the immunogenicity of tumors. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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19 pages, 4109 KiB

Open AccessArticle

Chemotherapy Shifts the Balance in Favor of CD8+ TNFR2+ TILs in Triple-Negative Breast Tumors

by Tamir Baram, Nofar Erlichman, Maya Dadiani, Nora Balint-Lahat, Anya Pavlovski, Tsipi Meshel, Dana Morzaev-Sulzbach, Einav Nili Gal-Yam, Iris Barshack and Adit Ben-Baruch

Cells 2021, 10(6), 1429; https://doi.org/10.3390/cells10061429 - 8 Jun 2021

Cited by 7 | Viewed by 3797

Abstract

Triple-negative breast cancer (TNBC) is primarily treated via chemotherapy; in parallel, efforts are made to introduce immunotherapies into TNBC treatment. CD4+ TNFR2+ lymphocytes were reported as Tregs that contribute to tumor progression. However, our published study indicated that TNFR2+ tumor-infiltrating lymphocytes (TNFR2+ TILs) [...] Read more.

Triple-negative breast cancer (TNBC) is primarily treated via chemotherapy; in parallel, efforts are made to introduce immunotherapies into TNBC treatment. CD4+ TNFR2+ lymphocytes were reported as Tregs that contribute to tumor progression. However, our published study indicated that TNFR2+ tumor-infiltrating lymphocytes (TNFR2+ TILs) were associated with improved survival in TNBC patient tumors. Based on our analyses of the contents of CD4+ and CD8+ TILs in TNBC patient tumors, in the current study, we determined the impact of chemotherapy on CD4+ and CD8+ TIL subsets in TNBC mouse tumors. We found that chemotherapy led to (1) a reduction in CD4+ TNFR2+ FOXP3+ TILs, indicating that chemotherapy decreased the content of CD4+ TNFR2+ Tregs, and (2) an elevation in CD8+ TNFR2+ and CD8+ TNFR2+ PD-1+ TILs; high levels of these two subsets were significantly associated with reduced tumor growth. In spleens of tumor-bearing mice, chemotherapy down-regulated CD4+ TNFR2+ FOXP3+ cells but the subset of CD8+ TNFR2+ PD-1+ was not present prior to chemotherapy and was not increased by the treatment. Thus, our data suggest that chemotherapy promotes the proportion of protective CD8+ TNFR2+ TILs and that, unlike other cancer types, therapeutic strategies directed against TNFR2 may be detrimental in TNBC. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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21 pages, 5830 KiB

Open AccessArticle

Anticancer Effects of Sublingual Type I IFN in Combination with Chemotherapy in Implantable and Spontaneous Tumor Models

by Maria Ciccolella, Sara Andreone, Jacopo Mancini, Paola Sestili, Donatella Negri, Anna Maria Pacca, Maria Teresa D’Urso, Daniele Macchia, Rossella Canese, Ken Pang, Thomas SaiYing Ko, Yves Decadt, Giovanna Schiavoni, Fabrizio Mattei, Filippo Belardelli, Eleonora Aricò and Laura Bracci

Cells 2021, 10(4), 845; https://doi.org/10.3390/cells10040845 - 8 Apr 2021

Cited by 4 | Viewed by 3397

Abstract

Salivary gland tumors are a heterogeneous group of neoplasms representing less than 10% of all head and neck tumors. Among salivary gland tumors, salivary duct carcinoma (SDC) is a rare, but highly aggressive malignant tumor resembling ductal breast carcinoma. Sublingual treatments are promising [...] Read more.

Salivary gland tumors are a heterogeneous group of neoplasms representing less than 10% of all head and neck tumors. Among salivary gland tumors, salivary duct carcinoma (SDC) is a rare, but highly aggressive malignant tumor resembling ductal breast carcinoma. Sublingual treatments are promising for SDC due to the induction of both local and systemic biological effects and to reduced systemic toxicity compared to other administration routes. In the present study, we first established that the sublingual administration of type I IFN (IFN-I) is safe and feasible, and exerts antitumor effects both as monotherapy and in combination with chemotherapy in transplantable tumor models, i.e., B16-OVA melanoma and EG.7-OVA lymphoma. Subsequently, we proved that sublingual IFN-I in combination with cyclophosphamide (CTX) induces a long-lasting reduction of tumor mass in NeuT transgenic mice that spontaneously develop SDC. Most importantly, tumor shrinkage in NeuT transgenic micewas accompanied by the emergence of tumor-specific cellular immune responses both in the blood and in the tumor tissue. Altogether, these results provide evidence that sublingual IFN holds promise in combination with chemotherapy for the treatment of cancer. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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48 pages, 8579 KiB

Open AccessArticle

A New Epigenetic Model to Stratify Glioma Patients According to Their Immunosuppressive State

by Maurizio Polano, Emanuele Fabbiani, Eva Andreuzzi, Federica Di Cintio, Luca Bedon, Davide Gentilini, Maurizio Mongiat, Tamara Ius, Mauro Arcicasa, Miran Skrap, Michele Dal Bo and Giuseppe Toffoli

Cells 2021, 10(3), 576; https://doi.org/10.3390/cells10030576 - 5 Mar 2021

Cited by 9 | Viewed by 5284

Abstract

Gliomas are the most common primary neoplasm of the central nervous system. A promising frontier in the definition of glioma prognosis and treatment is represented by epigenetics. Furthermore, in this study, we developed a machine learning classification model based on epigenetic data (CpG [...] Read more.

Gliomas are the most common primary neoplasm of the central nervous system. A promising frontier in the definition of glioma prognosis and treatment is represented by epigenetics. Furthermore, in this study, we developed a machine learning classification model based on epigenetic data (CpG probes) to separate patients according to their state of immunosuppression. We considered 573 cases of low-grade glioma (LGG) and glioblastoma (GBM) from The Cancer Genome Atlas (TCGA). First, from gene expression data, we derived a novel binary indicator to flag patients with a favorable immune state. Then, based on previous studies, we selected the genes related to the immune state of tumor microenvironment. After, we improved the selection with a data-driven procedure, based on Boruta. Finally, we tuned, trained, and evaluated both random forest and neural network classifiers on the resulting dataset. We found that a multi-layer perceptron network fed by the 338 probes selected by applying both expert choice and Boruta results in the best performance, achieving an out-of-sample accuracy of 82.8%, a Matthews correlation coefficient of 0.657, and an area under the ROC curve of 0.9. Based on the proposed model, we provided a method to stratify glioma patients according to their epigenomic state. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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17 pages, 4310 KiB

Open AccessArticle

Tumor Necrosis Factor Receptor-1 (p55) Deficiency Attenuates Tumor Growth and Intratumoral Angiogenesis and Stimulates CD8⁺ T Cell Function in Melanoma

by Yamila I. Rodriguez, Ludmila E. Campos, Melina G. Castro, Nadia Bannoud, Ada G. Blidner, Verónica P. Filippa, Diego O. Croci, Gabriel A. Rabinovich and Sergio E. Alvarez

Cells 2020, 9(11), 2469; https://doi.org/10.3390/cells9112469 - 13 Nov 2020

Cited by 9 | Viewed by 3471

Abstract

The role of tumor necrosis factor-α (TNF-α) in shaping the tumor microenvironment is ambiguous. Consistent with its uncertain role in melanoma, TNF-α plays a dual role, either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment. TNF-α signals via two cognate [...] Read more.

The role of tumor necrosis factor-α (TNF-α) in shaping the tumor microenvironment is ambiguous. Consistent with its uncertain role in melanoma, TNF-α plays a dual role, either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment. TNF-α signals via two cognate receptors, namely TNFR1 (p55) and TNFR2 (p75), which mediate divergent biological activities. Here, we analyzed the impact of TNFR1 deficiency in tumor progression in the B16.F1 melanoma model. Tumors developed in mice lacking TNFR1 (TNFR1 knock-out; KO) were smaller and displayed lower proliferation compared to their wild type (WT) counterpart. Moreover, TNFR1 KO mice showed reduced tumor angiogenesis. Although no evidence of spontaneous metastases was observed, conditioned media obtained from TNFR1 KO tumors increased tumor cell migration. Whereas the analysis of tumor-associated immune cell infiltrates showed similar frequency of total and M2-polarized tumor-associated macrophages (TAMs), the percentage of CD8⁺ T cells was augmented in TNFR1 KO tumors. Indeed, functional ex vivo assays demonstrated that CD8⁺ T cells obtained from TNFR1KO mice displayed an increased cytotoxic function. Thus, lack of TNFR1 attenuates melanoma growth by modulating tumor cell proliferation, migration, angiogenesis and CD8⁺ T cell accumulation and activation, suggesting that interruption of TNF-TNFR1 signaling may contribute to control tumor burden. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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17 pages, 2571 KiB

Open AccessArticle

Equine Penile Squamous Cell Carcinomas as a Model for Human Disease: A Preliminary Investigation on Tumor Immune Microenvironment

by Ilaria Porcellato, Samanta Mecocci, Luca Mechelli, Katia Cappelli, Chiara Brachelente, Marco Pepe, Margherita Orlandi, Rodolfo Gialletti, Benedetta Passeri, Angelo Ferrari, Paola Modesto, Alessandro Ghelardi and Elisabetta Razzuoli

Cells 2020, 9(11), 2364; https://doi.org/10.3390/cells9112364 - 27 Oct 2020

Cited by 12 | Viewed by 3217

Abstract

Penile squamous cell carcinomas (SCCs) are common tumors in older horses, with poor prognosis mostly due to local invasion and recurrence. These tumors are thought to be mainly caused by Equus caballus papillomavirus type 2 (EcPV-2). The aim of this study is to [...] Read more.

Penile squamous cell carcinomas (SCCs) are common tumors in older horses, with poor prognosis mostly due to local invasion and recurrence. These tumors are thought to be mainly caused by Equus caballus papillomavirus type 2 (EcPV-2). The aim of this study is to characterize the tumor immune environment (TIME) in equine penile tumors. Equine penile epithelial tumors (17 epSCCs; 2 carcinomas in situ, CIS; 1 papilloma, P) were retrospectively selected; immune infiltrate was assessed by histology and immunohistochemistry; RT-qPCR tested the expression of selected chemokines and EcPV-2 DNA and RNA. The results confirmed EcPV-2-L1 DNA in 18/20 (90%) samples. L1 expression was instead retrieved in 13/20 cases (65%). The samples showed an increased infiltration of CD3⁺lymphocytes, macrophages (MAC387; IBA1), plasma cells (MUM1), and FoxP3⁺lymphocytes in the intra/peritumoral stroma when compared to extratumoral tissues (p < 0.05). Only MAC387⁺neutrophils were increased in EcPV-2^high viral load samples (p < 0.05). IL12/p35 was differentially expressed in EcPV^high and EcPV^low groups (p = 0.007). A significant decrease of IFNG and IL2 expression was highlighted in TGFB1-positive samples (p < 0.05). IBA1 and CD20 were intratumorally increased in cases where IL-10 was expressed (p < 0.005). EpSCCs may represent a good spontaneous model for the human counterpart. Further prospective studies are needed in order to confirm these preliminary results. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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7 pages, 229 KiB

Open AccessArticle

Systemic Inflammatory Markers Are Predictive of the Response to Brachytherapy in the Prostate

by Daniel Taussky, Denis Soulieres, Miguel Chagnon, Guila Delouya and Houda Bahig

Cells 2020, 9(10), 2153; https://doi.org/10.3390/cells9102153 - 23 Sep 2020

Cited by 3 | Viewed by 1924

Abstract

We analyzed the influence of the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) on the biochemical recurrence (BCR) in low-intermediate risk prostate cancer (PCa). A total of 604 patients treated with exclusive brachytherapy for low- and intermediate-risk cancers were included in this study. [...] Read more.

We analyzed the influence of the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) on the biochemical recurrence (BCR) in low-intermediate risk prostate cancer (PCa). A total of 604 patients treated with exclusive brachytherapy for low- and intermediate-risk cancers were included in this study. No patient received either androgen deprivation or brachytherapy as a boost. BCR was defined according to the Phoenix definition (nadir prostatic specific antigen (PSA) +2). The median follow-up was 60 months (IQR 44–48 months). An NLR > 3 was more frequent in statin users (p = 0.025), but not in diabetics (p = 0.079). In univariate analysis (UVA) and multivariate analysis (MVA), a NLR > 3 (MVA p = 0.03), as well as Cancer of the Prostate Risk Assessment (CAPRA) low- vs. intermediate-risk (MVA p = 0.04), were predictive of BCR. When combining the NLR score with the CAPRA risk group, CAPRA intermediate risk patients with an NLR ≤ 3 (n = 157) had the worst (p = 0.0276) BCR rates, with a 5-year recurrence-free survival (p = 0.004, Bonferroni correction for six comparisons p = 0.024). We were able to identify a subgroup of PCa patients with CAPRA intermediate-risk and an NLR ≤ 3 who had worse BCR. This is in contrast to most other cancers, which have a worse prognosis when the NLR is high. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

20 pages, 2338 KiB

Open AccessArticle

Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer

by Jihane Boustani, Valentin Derangère, Aurélie Bertaut, Olivier Adotevi, Véronique Morgand, Céline Charon-Barra, François Ghiringhelli and Céline Mirjolet

Cells 2020, 9(9), 2071; https://doi.org/10.3390/cells9092071 - 10 Sep 2020

Cited by 15 | Viewed by 2742

Abstract

In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data [...] Read more.

In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data from biopsies and surgical specimens in 74 patients. The main objective was to evaluate the impact of neoadjuvant RT and fractionation on PD-L1 expression. Secondary objectives were to study the relation between PD-L1 expression and tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and CD8 TILs infiltration. Median rates of cells expressing PD-L1 pre- and post-RT were 0.15 (range, 0–17) and 0.5 (range, 0–27.5), respectively (p = 0.0005). There was no effect of RT fractionation on PD-L1+ cell rates. We found no relation between CD8+ TILs infiltration and PD-L1 expression and no difference between high-PD-L1 or low-PD-L1 expression and TRG. High-to-high PD-L1 expression profile had none significant higher OS and PFS compared to all other groups (p = 0.06). Median OS and PFS were higher in biopsies with >0.08 PD-L1+ cells. High-to-high PD-L1 profile and ypT0-2 were significantly associated with higher OS and PFS. This study did not show the differential induction of PD-L1 expression according to fractionation. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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13 pages, 1406 KiB

Open AccessArticle

HLA Expression Correlates to the Risk of Immune Checkpoint Inhibitor-Induced Pneumonitis

by Pierpaolo Correale, Rita Emilena Saladino, Diana Giannarelli, Andrea Sergi, Maria Antonietta Mazzei, Giovanna Bianco, Rocco Giannicola, Eleonora Iuliano, Iris Maria Forte, Natale Daniele Calandruccio, Antonia Consuelo Falzea, Alessandra Strangio, Valerio Nardone, Pierpaolo Pastina, Paolo Tini, Amalia Luce, Michele Caraglia, Daniele Caracciolo, Luciano Mutti, Pierfrancesco Tassone, Luigi Pirtoli, Antonio Giordano and Pierosandro Tagliaferri Show full author list Hide full author list

Cells 2020, 9(9), 1964; https://doi.org/10.3390/cells9091964 - 25 Aug 2020

Cited by 35 | Viewed by 5027

Abstract

Tumor-infiltrating T cell rescue by programmed cell death receptor-1 (PD-1)/PD-1 ligand-1 (PD-L1) immune checkpoint blockade is a recommended treatment for malignant diseases, including metastatic non-small-cell lung cancer (mNSCLC), malignant melanoma (MM), head and neck, kidney, and urothelial cancer. Monoclonal antibodies (mAbs) against either [...] Read more.

Tumor-infiltrating T cell rescue by programmed cell death receptor-1 (PD-1)/PD-1 ligand-1 (PD-L1) immune checkpoint blockade is a recommended treatment for malignant diseases, including metastatic non-small-cell lung cancer (mNSCLC), malignant melanoma (MM), head and neck, kidney, and urothelial cancer. Monoclonal antibodies (mAbs) against either PD-1 or PD-L1 are active agents for these patients; however, their use may be complicated by unpredictable immune-related adverse events (irAEs), including immune-related pneumonitis (IRP). We carried out a retrospective multi-institutional statistical analysis to investigate clinical and biological parameters correlated with IRP rate on a cohort of 256 patients who received real-world treatment with PD-1/PD-L1 blocking mAbs. An independent radiological review board detected IRP in 29 patients. We did not find statistical IRP rate correlation with gender, tumor type, specific PD-1 or PD-L1 blocking mAbs, radiation therapy, inflammatory profile, or different irAEs. A higher IRP risk was detected only in mNSCLC patients who received metronomic chemotherapy +/− bevacizumab compared with other treatments prior PD-1/PD-L1 blockade. Moreover, we detected a strong correlation among the IRP rate and germinal expression of HLA-B*35 and DRB1*11, alleles associated to autoimmune diseases. Our findings may have relevant implications in predicting the IRP rate in mNSCLC patients receiving PD-1/PD-L1 blockade and need to be validated on a larger patient series. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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17 pages, 2805 KiB

Open AccessArticle

Inter-Tumor Heterogeneity—Melanomas Respond Differently to GM-CSF-Mediated Activation

by Adi Moshe, Sivan Izraely, Orit Sagi-Assif, Sapir Malka, Shlomit Ben-Menachem, Tsipi Meshel, Metsada Pasmanik-Chor, Dave S.B. Hoon and Isaac P. Witz

Cells 2020, 9(7), 1683; https://doi.org/10.3390/cells9071683 - 13 Jul 2020

Cited by 10 | Viewed by 3124

Abstract

Granulocyte-monocyte colony stimulating factor (GM-CSF) is used as an adjuvant in various clinical and preclinical studies with contradictory results. These were attributed to opposing effects of GM-CSF on the immune or myeloid systems of the treated patients or to lack of optimal dosing [...] Read more.

Granulocyte-monocyte colony stimulating factor (GM-CSF) is used as an adjuvant in various clinical and preclinical studies with contradictory results. These were attributed to opposing effects of GM-CSF on the immune or myeloid systems of the treated patients or to lack of optimal dosing regimens. The results of the present study point to inter-tumor heterogeneity as a possible mechanism accounting for the contrasting responses to GM-CSF incorporating therapies. Employing xenograft models of human melanomas in nude mice developed in our lab, we detected differential functional responses of melanomas from different patients to GM-CSF both in vitro as well as in vivo. Whereas cells of one melanoma acquired pro metastatic features following exposure to GM-CSF, cells from another melanoma either did not respond or became less malignant. We propose that inter-melanoma heterogeneity as manifested by differential responses of melanoma cells (and perhaps also of other tumor) to GM-CSF may be developed into a predictive marker providing a tool to segregate melanoma patients who will benefit from GM-CSF therapy from those who will not. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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21 pages, 5505 KiB

Open AccessArticle

Basophils from Cancer Patients Respond to Immune Stimuli and Predict Clinical Outcome

by Heather J. Bax, Jitesh Chauhan, Chara Stavraka, Atousa Khiabany, Mano Nakamura, Giulia Pellizzari, Kristina M. Ilieva, Sara Lombardi, Hannah J. Gould, Christopher J. Corrigan, Stephen J. Till, Sidath Katugampola, Paul S. Jones, Claire Barton, Anna Winship, Sharmistha Ghosh, Ana Montes, Debra H. Josephs, James F. Spicer and Sophia N. Karagiannis

Cells 2020, 9(7), 1631; https://doi.org/10.3390/cells9071631 - 7 Jul 2020

Cited by 27 | Viewed by 6519

Abstract

Basophils are involved in manifestations of hypersensitivity, however, the current understanding of their propensity for activation and their prognostic value in cancer patients remains unclear. As in healthy and atopic individuals, basophil populations were identified in blood from ovarian cancer patients (n [...] Read more.

Basophils are involved in manifestations of hypersensitivity, however, the current understanding of their propensity for activation and their prognostic value in cancer patients remains unclear. As in healthy and atopic individuals, basophil populations were identified in blood from ovarian cancer patients (n = 53) with diverse tumor histologies and treatment histories. Ex vivo basophil activation was measured by CD63 expression using the basophil activation test (BAT). Irrespective of prior treatment, basophils could be activated by stimulation with IgE- (anti-FcεRI and anti-IgE) and non-IgE (fMLP) mediated triggers. Basophil activation was detected by ex vivo exposure to paclitaxel, but not to other anti-cancer therapies, in agreement with a clinical history of systemic hypersensitivity reactions to paclitaxel. Protein and gene expression analyses support the presence of basophils (CCR3, CD123, FcεRI) and activated basophils (CD63, CD203c, tryptase) in ovarian tumors. Greater numbers of circulating basophils, cells with greater capacity for ex vivo stimulation (n = 35), and gene signatures indicating the presence of activated basophils in tumors (n = 439) were each associated with improved survival in ovarian cancer. Circulating basophils in cancer patients respond to IgE- and non-IgE-mediated signals and could help identify hypersensitivity to therapeutic agents. Activated circulating and tumor-infiltrating basophils may be potential biomarkers in oncology. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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Review

Jump to: Editorial, Research

22 pages, 3617 KiB

Open AccessFeature PaperReview

Acidic and Hypoxic Microenvironment in Melanoma: Impact of Tumour Exosomes on Disease Progression

by Zaira Boussadia, Adriana Rosa Gambardella, Fabrizio Mattei and Isabella Parolini

Cells 2021, 10(12), 3311; https://doi.org/10.3390/cells10123311 - 25 Nov 2021

Cited by 15 | Viewed by 3766

Abstract

The mechanisms of melanoma progression have been extensively studied in the last decade, and despite the diagnostic and therapeutic advancements pursued, malignant melanoma still accounts for 60% of skin cancer deaths. Therefore, research efforts are required to better define the intercellular molecular steps [...] Read more.

The mechanisms of melanoma progression have been extensively studied in the last decade, and despite the diagnostic and therapeutic advancements pursued, malignant melanoma still accounts for 60% of skin cancer deaths. Therefore, research efforts are required to better define the intercellular molecular steps underlying the melanoma development. In an attempt to represent the complexity of the tumour microenvironment (TME), here we analysed the studies on melanoma in acidic and hypoxic microenvironments and the interactions with stromal and immune cells. Within TME, acidity and hypoxia force melanoma cells to adapt and to evolve into a malignant phenotype, through the cooperation of the tumour-surrounding stromal cells and the escape from the immune surveillance. The role of tumour exosomes in the intercellular crosstalk has been generally addressed, but less studied in acidic and hypoxic conditions. Thus, this review aims to summarize the role of acidic and hypoxic microenvironment in melanoma biology, as well as the role played by melanoma-derived exosomes (Mexo) under these conditions. We also present a perspective on the characteristics of acidic and hypoxic exosomes to disclose molecules, to be further considered as promising biomarkers for an early detection of the disease. An update on the use of exosomes in melanoma diagnosis, prognosis and response to treatment will be also provided and discussed. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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15 pages, 1894 KiB

Open AccessReview

Neutropenia and Large Granular Lymphocyte Leukemia: From Pathogenesis to Therapeutic Options

by Giulia Calabretto, Antonella Teramo, Gregorio Barilà, Cristina Vicenzetto, Vanessa Rebecca Gasparini, Gianpietro Semenzato and Renato Zambello

Cells 2021, 10(10), 2800; https://doi.org/10.3390/cells10102800 - 19 Oct 2021

Cited by 20 | Viewed by 4935

Abstract

Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made [...] Read more.

Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular STAT3 mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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20 pages, 1806 KiB

Open AccessReview

The Immune Privilege of Cancer Stem Cells: A Key to Understanding Tumor Immune Escape and Therapy Failure

by Claudia Galassi, Martina Musella, Nicoletta Manduca, Ester Maccafeo and Antonella Sistigu

Cells 2021, 10(9), 2361; https://doi.org/10.3390/cells10092361 - 8 Sep 2021

Cited by 40 | Viewed by 5321

Abstract

Cancer stem cells (CSCs) are broadly considered immature, multipotent, tumorigenic cells within the tumor mass, endowed with the ability to self-renew and escape immune control. All these features contribute to place CSCs at the pinnacle of tumor aggressiveness and (immune) therapy resistance. The [...] Read more.

Cancer stem cells (CSCs) are broadly considered immature, multipotent, tumorigenic cells within the tumor mass, endowed with the ability to self-renew and escape immune control. All these features contribute to place CSCs at the pinnacle of tumor aggressiveness and (immune) therapy resistance. The immune privileged status of CSCs is induced and preserved by various mechanisms that directly affect them (e.g., the downregulation of the major histocompatibility complex class I) and indirectly are induced in the host immune cells (e.g., activation of immune suppressive cells). Therefore, deeper insights into the immuno-biology of CSCs are essential in our pursuit to find new therapeutic opportunities that eradicate cancer (stem) cells. Here, we review and discuss the ability of CSCs to evade the innate and adaptive immune system, as we offer a view of the immunotherapeutic strategies adopted to potentiate and address specific subsets of (engineered) immune cells against CSCs. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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22 pages, 843 KiB

Open AccessReview

Osteoimmuno-Oncology: Therapeutic Opportunities for Targeting Immune Cells in Bone Metastasis

by Tiina E. Kähkönen, Jussi M. Halleen and Jenni Bernoulli

Cells 2021, 10(6), 1529; https://doi.org/10.3390/cells10061529 - 17 Jun 2021

Cited by 13 | Viewed by 4253

Abstract

Immunotherapies provide a potential treatment option for currently incurable bone metastases. Bone marrow is an important secondary lymphoid organ with a unique immune contexture. Even at non-disease state immune cells and bone cells interact with each other, bone cells supporting the development of [...] Read more.

Immunotherapies provide a potential treatment option for currently incurable bone metastases. Bone marrow is an important secondary lymphoid organ with a unique immune contexture. Even at non-disease state immune cells and bone cells interact with each other, bone cells supporting the development of immune cells and immune cells regulating bone turnover. In cancer, tumor cells interfere with this homeostatic process starting from formation of pre-metastatic niche and later supporting growth of bone metastases. In this review, we introduce a novel concept osteoimmuno-oncology (OIO), which refers to interactions between bone, immune and tumor cells in bone metastatic microenvironment. We also discuss therapeutic opportunities of targeting immune cells in bone metastases, and associated efficacy and safety concerns. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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25 pages, 3122 KiB

Open AccessReview

The Interplay between the Immune and the Endocannabinoid Systems in Cancer

by Mariantonia Braile, Simone Marcella, Gianni Marone, Maria Rosaria Galdiero, Gilda Varricchi and Stefania Loffredo

Cells 2021, 10(6), 1282; https://doi.org/10.3390/cells10061282 - 21 May 2021

Cited by 34 | Viewed by 11063

Abstract

The therapeutic potential of Cannabis sativa has been recognized since ancient times. Phytocannabinoids, endocannabinoids and synthetic cannabinoids activate two major G protein-coupled receptors, subtype 1 and 2 (CB1 and CB2). Cannabinoids (CBs) modulate several aspects of cancer cells, such as apoptosis, autophagy, proliferation, [...] Read more.

The therapeutic potential of Cannabis sativa has been recognized since ancient times. Phytocannabinoids, endocannabinoids and synthetic cannabinoids activate two major G protein-coupled receptors, subtype 1 and 2 (CB1 and CB2). Cannabinoids (CBs) modulate several aspects of cancer cells, such as apoptosis, autophagy, proliferation, migration, epithelial-to-mesenchymal transition and stemness. Moreover, agonists of CB1 and CB2 receptors inhibit angiogenesis and lymphangiogenesis in vitro and in vivo. Low-grade inflammation is a hallmark of cancer in the tumor microenvironment (TME), which contains a plethora of innate and adaptive immune cells. These cells play a central role in tumor initiation and growth and the formation of metastasis. CB2 and, to a lesser extent, CB1 receptors are expressed on a variety of immune cells present in TME (e.g., T cells, macrophages, mast cells, neutrophils, NK cells, dendritic cells, monocytes, eosinophils). The activation of CB receptors modulates a variety of biological effects on cells of the adaptive and innate immune system. The expression of CB2 and CB1 on different subsets of immune cells in TME and hence in tumor development is incompletely characterized. The recent characterization of the human cannabinoid receptor CB2-G_i signaling complex will likely aid to design potent and specific CB2/CB1 ligands with therapeutic potential in cancer. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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8 pages, 1675 KiB

Open AccessReview

Novel Immune Stimulant Amplifies Direct Tumoricidal Effect of Cancer Ablation Therapies and Their Systemic Antitumor Immune Efficacy

by Mladen Korbelik, Tomas Hode, Samuel S. K. Lam and Wei R. Chen

Cells 2021, 10(3), 492; https://doi.org/10.3390/cells10030492 - 25 Feb 2021

Cited by 17 | Viewed by 4169

Abstract

Ablation therapies have emerged as an effective tool for destroying cancerous tissue, but for advanced and disseminated tumors their application remains mainly a palliative measure. However, it is becoming increasingly clear that this limitation can be redressed by the use of intratumoral immune [...] Read more.

Ablation therapies have emerged as an effective tool for destroying cancerous tissue, but for advanced and disseminated tumors their application remains mainly a palliative measure. However, it is becoming increasingly clear that this limitation can be redressed by the use of intratumoral immune stimulating agents for amplifying potential antitumor immune responses that are induced by ablation therapies. A novel immune stimulating drug IP-001, a specific variant of the N-dihydrogalactochitosan (GC) family of molecules, has shown to be effective against metastatic tumors, when combined with different forms tumor ablation. It acts as a multi-function immune stimulant both by directly inhibiting cell membrane repair and recycling of ablation-damaged tumor cells, and indirectly by sequestering ablation-released tumor antigens, as well as recruiting and stimulating antigen presenting cells to induce a potent Th1 type T cell response against the cancer. In this review, we briefly discuss the current applications of local ablation for cancer treatment and the effects of GC in combination with other ablation therapies, a therapeutic approach that is pioneering the field of Interventional Immuno-Oncology (IIO). Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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16 pages, 987 KiB

Open AccessFeature PaperReview

Neuroimmune Regulation of Surgery-Associated Metastases

by Michael R. Shurin, James H. Baraldi and Galina V. Shurin

Cells 2021, 10(2), 454; https://doi.org/10.3390/cells10020454 - 20 Feb 2021

Cited by 13 | Viewed by 3874

Abstract

Surgery remains an essential therapeutic approach for most solid malignancies. Although for more than a century accumulating clinical and experimental data have indicated that surgical procedures themselves may promote the appearance and progression of recurrent and metastatic lesions, only in recent years has [...] Read more.

Surgery remains an essential therapeutic approach for most solid malignancies. Although for more than a century accumulating clinical and experimental data have indicated that surgical procedures themselves may promote the appearance and progression of recurrent and metastatic lesions, only in recent years has renewed interest been taken in the mechanism by which metastasizing of cancer occurs following operative procedures. It is well proven now that surgery constitutes a risk factor for the promotion of pre-existing, possibly dormant micrometastases and the acceleration of new metastases through several mechanisms, including the release of neuroendocrine and stress hormones and wound healing pathway-associated immunosuppression, neovascularization, and tissue remodeling. These postoperative consequences synergistically facilitate the establishment of new metastases and the development of pre-existing micrometastases. While only in recent years the role of the peripheral nervous system has been recognized as another contributor to cancer development and metastasis, little is known about the contribution of tumor-associated neuronal and neuroglial elements in the metastatic disease related to surgical trauma and wound healing. Specifically, although numerous clinical and experimental data suggest that biopsy- and surgery-induced wound healing can promote survival and metastatic spread of residual and dormant malignant cells, the involvement of the tumor-associated neuroglial cells in the formation of metastases following tissue injury has not been well understood. Understanding the clinical significance and underlying mechanisms of neuroimmune regulation of surgery-associated metastasis will not only advance the field of neuro–immuno–oncology and contribute to basic science and translational oncology research but will also produce a strong foundation for developing novel mechanism-based therapeutic approaches that may protect patients against the oncologically adverse effects of primary tumor biopsy and excision. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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17 pages, 1783 KiB

Open AccessReview

Natural Compounds of Marine Origin as Inducers of Immunogenic Cell Death (ICD): Potential Role for Cancer Interception and Therapy

by Clementina Sansone, Antonino Bruno, Concetta Piscitelli, Denisa Baci, Angelo Fontana, Christophe Brunet, Douglas M. Noonan and Adriana Albini

Cells 2021, 10(2), 231; https://doi.org/10.3390/cells10020231 - 25 Jan 2021

Cited by 35 | Viewed by 7114

Abstract

Regulated cell death (RCD) has always been considered a tolerogenic event. Immunogenic cell death (ICD) occurs as a consequence of tumour cell death accompanied by the release of damage-associated molecular patterns (DAMPs), triggering an immune response. ICD plays a major role in stimulating [...] Read more.

Regulated cell death (RCD) has always been considered a tolerogenic event. Immunogenic cell death (ICD) occurs as a consequence of tumour cell death accompanied by the release of damage-associated molecular patterns (DAMPs), triggering an immune response. ICD plays a major role in stimulating the function of the immune system in cancer during chemotherapy and radiotherapy. ICD can therefore represent one of the routes to boost anticancer immune responses. According to the recommendations of the Nomenclature Committee on Cell Death (2018), apoptosis (type I cell death) and necrosis (type II cell death) represent are not the only types of RCD, which also includes necroptosis, pyroptosis, ferroptosis and others. Specific downstream signalling molecules and death-inducing stimuli can regulate distinct forms of ICD, which develop and promote the immune cell response. Dying cells deliver different potential immunogenic signals, such as DAMPs, which are able to stimulate the immune system. The acute exposure of DAMPs can prime antitumour immunity by inducing activation of antigen-presenting cells (APC), such as dendritic cells (DC), leading to the downstream response by cytotoxic T cells and natural killer cells (NK). As ICD represents an important target to direct and develop new pharmacological interventions, the identification of bioactive natural products, which are endowed with low side effects, higher tolerability and preferentially inducing immunogenic programmed cell death, represents a priority in biomedical research. The ability of ICD to drive the immune response depends on two major factors, neither of which is intrinsic to cell death: ‘Antigenicity and adjuvanticity’. Indeed, the use of natural ICD-triggering molecules, alone or in combination with different (immuno)therapies, can result in higher efficacy and tolerability. Here, we focused on natural (marine) compounds, particularly on marine microalgae derived molecules such as exopolysaccharides, sulphated polysaccharides, glycopeptides, glycolipids, phospholipids, that are endowed with ICD-inducing properties and sulfavants. Here, we discuss novel and repurposed small-molecule ICD triggers, as well as their ability to target important molecular pathways including the IL-6, TNF-α and interferons (IFNs), leading to immune stimulation, which could be used alone or in combinatorial immunotherapeutic strategies in cancer prevention and therapies. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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13 pages, 284 KiB

Open AccessReview

The Potentiation of Anti-Tumor Immunity by Tumor Abolition with Alpha Particles, Protons, or Carbon Ion Radiation and Its Enforcement by Combination with Immunoadjuvants or Inhibitors of Immune Suppressor Cells and Checkpoint Molecules

by Yona Keisari and Itzhak Kelson

Cells 2021, 10(2), 228; https://doi.org/10.3390/cells10020228 - 25 Jan 2021

Cited by 26 | Viewed by 3981

Abstract

The delivery of radiation therapy (RT) for cancer with intent to cure has been optimized and standardized over the last 80 years. Both preclinical and clinical work emphasized the observation that radiation destroys the tumor and exposes its components to the immune response [...] Read more.

The delivery of radiation therapy (RT) for cancer with intent to cure has been optimized and standardized over the last 80 years. Both preclinical and clinical work emphasized the observation that radiation destroys the tumor and exposes its components to the immune response in a mode that facilitates the induction of anti-tumor immunity or reinforces such a response. External beam photon radiation is the most prevalent in situ abolition treatment, and its use exposed the “abscopal effect”. Particle radiotherapy (PRT), which has been in various stages of research and development for 70 years, is today available for the treatment of patients in the form of alpha particles, proton, or carbon ion radiotherapy. Charged particle radiotherapy is based on the acceleration of charged species, such as protons or carbon-12, which deposit their energy in the treated tumor and have a higher relative biological effectiveness compared with photon radiation. In this review, we will bring evidence that alpha particles, proton, or carbon ion radiation can destroy tumors and activate specific anti-tumor immune responses. Radiation may also directly affect the distribution and function of immune cells such as T cells, regulatory T cells, and mononuclear phagocytes. Tumor abolition by radiation can trigger an immune response against the tumor. However, abolition alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement abolition to reinforce the anti-tumor immunity to better eradicate residual local and metastatic tumor cells. Various methods and agents such as immunoadjuvants, suppressor cell inhibitors, or checkpoint inhibitors were used to manipulate the immune response in combination with radiation. This review deals with the manifestations of particle-mediated radiotherapy and its correlation with immunotherapy of cancer. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

21 pages, 1112 KiB

Open AccessReview

Tumor-Associated Antigen xCT and Mutant-p53 as Molecular Targets for New Combinatorial Antitumor Strategies

by Jolanda Magri, Alessandro Gasparetto, Laura Conti, Enzo Calautti, Chiara Cossu, Roberto Ruiu, Giuseppina Barutello and Federica Cavallo

Cells 2021, 10(1), 108; https://doi.org/10.3390/cells10010108 - 8 Jan 2021

Cited by 16 | Viewed by 7096

Abstract

The cystine/glutamate antiporter xCT is a tumor-associated antigen that has been newly identified in many cancer types. By participating in glutathione biosynthesis, xCT protects cancer cells from oxidative stress conditions and ferroptosis, and contributes to metabolic reprogramming, thus promoting tumor progression and chemoresistance. [...] Read more.

The cystine/glutamate antiporter xCT is a tumor-associated antigen that has been newly identified in many cancer types. By participating in glutathione biosynthesis, xCT protects cancer cells from oxidative stress conditions and ferroptosis, and contributes to metabolic reprogramming, thus promoting tumor progression and chemoresistance. Moreover, xCT is overexpressed in cancer stem cells. These features render xCT a promising target for cancer therapy, as has been widely reported in the literature and in our work on its immunotargeting. Interestingly, studies on the TP53 gene have revealed that both wild-type and mutant p53 induce the post-transcriptional down modulation of xCT, contributing to ferroptosis. Moreover, APR-246, a small molecule drug that can restore wild-type p53 function in cancer cells, has been described as an indirect modulator of xCT expression in tumors with mutant p53 accumulation, and is thus a promising drug to use in combination with xCT inhibition. This review summarizes the current knowledge of xCT and its regulation by p53, with a focus on the crosstalk of these two molecules in ferroptosis, and also considers some possible combinatorial strategies that can make use of APR-246 treatment in combination with anti-xCT immunotargeting. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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21 pages, 1002 KiB

Open AccessReview

Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development

by Hsiang-Wei Huang, Cheng-Chih Chang, Chia-Siu Wang and Kwang-Huei Lin

Cells 2021, 10(1), 67; https://doi.org/10.3390/cells10010067 - 4 Jan 2021

Cited by 41 | Viewed by 4641

Abstract

Gastrointestinal cancer is highly associated with inflammatory processes inducing the release of cytokines from cancer or immune cells, including interferons, interleukins, chemokines, colony-stimulating factors, and growth factors, which promote or suppress tumor progression. Inflammatory cytokines within the tumor microenvironment promote immune cell infiltration. [...] Read more.

Gastrointestinal cancer is highly associated with inflammatory processes inducing the release of cytokines from cancer or immune cells, including interferons, interleukins, chemokines, colony-stimulating factors, and growth factors, which promote or suppress tumor progression. Inflammatory cytokines within the tumor microenvironment promote immune cell infiltration. Infiltrating immune, and tumor-surrounding stromal cells support tumor growth, angiogenesis, metastasis, and immunosuppression through communication with inflammatory cytokines and cell adhesion molecules. Notably, infiltrating immune and tumor cells present immunosuppressive molecules, such as programmed death-ligand 1 (PD-L1) and CD80/CD86. Suppression of cytotoxic T cells promotes tumor avoidance of immune surveillance and greater malignancy. Moreover, glycosylation and sialylation of proteins hyperexpressed on the cancer cell surface have been shown to enhance immune escape and metastasis. Cytokine treatments and immune checkpoint inhibitors are widely used in clinical practice. However, the tumor microenvironment is a rapidly changing milieu involving several factors. In this review, we have provided a summary of the interactions of inflammation and cell adhesion molecules between cancer and other cell types, to improve understanding of the tumor microenvironment. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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17 pages, 1430 KiB

Open AccessReview

Function of TREM1 and TREM2 in Liver-Related Diseases

by Huifang Sun, Jianguo Feng and Liling Tang

Cells 2020, 9(12), 2626; https://doi.org/10.3390/cells9122626 - 7 Dec 2020

Cited by 34 | Viewed by 8661

Abstract

TREM1 and TREM2 are members of the triggering receptors expressed on myeloid cells (TREM) family. Both TREM1 and TREM2 are immunoglobulin superfamily receptors. Their main function is to identify foreign antigens and toxic substances, thereby adjusting the inflammatory response. In the liver, TREM1 [...] Read more.

TREM1 and TREM2 are members of the triggering receptors expressed on myeloid cells (TREM) family. Both TREM1 and TREM2 are immunoglobulin superfamily receptors. Their main function is to identify foreign antigens and toxic substances, thereby adjusting the inflammatory response. In the liver, TREM1 and TREM2 are expressed on non-parenchymal cells, such as liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, and cells which infiltrate the liver in response to injury including monocyte-derived macrophages and neutrophils. The function of TREM1 and TREM2 in inflammatory response depends on Toll-like receptor 4. TREM1 mainly augments inflammation during acute inflammation, while TREM2 mainly inhibits chronic inflammation to protect the liver from pathological changes. Chronic inflammation often induces metabolic abnormalities, fibrosis, and tumorigenesis. The above physiological changes lead to liver-related diseases, such as liver injury, nonalcoholic steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma. Here, we review the function of TREM1 and TREM2 in different liver diseases based on inflammation, providing a more comprehensive perspective for the treatment of liver-related diseases. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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16 pages, 847 KiB

Open AccessReview

Intratumoral versus Circulating Lymphoid Cells as Predictive Biomarkers in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Is the Easiest Path the Best One?

by Marta Gascón, Dolores Isla, Mara Cruellas, Eva M. Gálvez, Rodrigo Lastra, Maitane Ocáriz, José Ramón Paño, Ariel Ramírez, Andrea Sesma, Irene Torres-Ramón, Alfonso Yubero, Julián Pardo and Luis Martínez-Lostao

Cells 2020, 9(6), 1525; https://doi.org/10.3390/cells9061525 - 22 Jun 2020

Cited by 15 | Viewed by 3818

Abstract

The molecular and cell determinants that modulate immune checkpoint (ICI) efficacy in lung cancer are still not well understood. However, there is a necessity to select those patients that will most benefit from these new treatments. Recent studies suggest the presence and/or the [...] Read more.

The molecular and cell determinants that modulate immune checkpoint (ICI) efficacy in lung cancer are still not well understood. However, there is a necessity to select those patients that will most benefit from these new treatments. Recent studies suggest the presence and/or the relative balance of specific lymphoid cells in the tumor microenvironment (TEM) including the T cell (activated, memory, and regulatory) and NK cell (CD56dim/bright) subsets, and correlate with a better response to ICI. The analyses of these cell subsets in peripheral blood, as a more accessible and homogeneous sample, might facilitate clinical decisions concerning fast prediction of ICI efficacy. Despite recent studies suggesting that lymphoid circulating cells might correlate with ICI efficacy and toxicity, more analyses and investigation are required to confirm if circulating lymphoid cells are a relevant picture of the lung TME and could be instrumental as ICI response biomarkers. This short review is aimed to discuss the recent advances in this fast-growing field. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities)

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