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Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid...
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Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: 30 September 2024 | Viewed by 8716

Special Issue Editor

Dr. Nuria Romero-Laorden

E-Mail Website
Guest Editor
Cátedra UAM-Fundación Instituto Roche de Medicina Personalizada de Precisión, Hospital Universitario de la Princesa, 62 Diego de León, Madrid, Spain
Interests: clinical cancer research; biomarkers; genitourinary cancer

Special Issue Information

Dear Colleagues,

Immunotherapy has revolutionized the treatment of cancer in recent years. Specifically, immune checkpoint inhibitors targeted to PD-1 or its ligand PD-L1 have changed the evolution of aggressive solid tumors, such as advanced lung cancer or melanoma. However, despite promising results, current immunotherapy is not effective for all patients, and therefore there is an urgent need for biomarker selection.  PD-L1 measured by immunohistochemistry has demonstrated a correlation between expression and survival in some clinical trials, but these results have not been able to be validated for all types of tumors and may vary depending on the antibody used in the different studies. Other tissue biomarkers, such as tumor mutational burden (TMB) or DNA repair defects (DRD), have been explored, yielding controversial results. Some studies have reported that these alterations may release a higher number of tumor neoantigens, thus leading to an increased activation of the immune system and a greater benefit in terms of immunotherapy response. Another type of approach is to identify patient-dependent predictors of immunotherapy efficacy, such as the development of immune-related side effects or the identification of changes in immune phenotype. It may be particularly interesting to detect biomarkers in real time at different points of disease evolution to examine the constant dynamic changes of the immune system. This Special Issue will highlight the current complex uses of biomarkers in clinical practice and to identify new potential immune biomarkers in solid tumors.

Dr. Nuria Romero-Laorden
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immunotherapy
  • checkpoint inhibitors
  • biomarkers
  • immune biomarkers
  • PD-L1
  • TMB
  • solid tumors

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Published Papers (6 papers)

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Research

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13 pages, 2509 KiB  
Article
Real-World Prevalence and Tolerability of Immune-Related Adverse Events in Older Adults with Non-Small Cell Lung Cancer: A Multi-Institutional Retrospective Study
by Ryosuke Matsukane, Takahiro Oyama, Ryosuke Tatsuta, Sakiko Kimura, Kojiro Hata, Shuhei Urata and Hiroyuki Watanabe
Cancers 2024, 16(11), 2159; https://doi.org/10.3390/cancers16112159 - 6 Jun 2024
Viewed by 1160
Abstract
With cancer diagnosis occurring at older ages, the use of immune checkpoint inhibitors (ICIs) has extended to older adults. However, the safety of immune-related adverse events (irAEs) in this population remains unclear and relies on data extrapolated from younger adults. This multicenter retrospective [...] Read more.
With cancer diagnosis occurring at older ages, the use of immune checkpoint inhibitors (ICIs) has extended to older adults. However, the safety of immune-related adverse events (irAEs) in this population remains unclear and relies on data extrapolated from younger adults. This multicenter retrospective study aimed to examine irAE prevalence and tolerability in older adults. We included 436 patients with non-small lung cancer undergoing ICI therapy and dichotomized them into two age groups (< or ≥75 years). Incidence of any irAE grade, grade ≥3 irAEs, and steroid usage after irAE occurrence was similar between younger (n = 332) and older groups (n = 104). While the younger patients with irAEs showed prolonged overall survival in the 12-month landmark Kaplan–Meier analysis (Hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.38–0.89, p = 0.013), the older cohort did not (HR 0.80, 95% CI 0.36–1.78, p = 0.588). Although no differences were observed with ICI continuation or re-challenge after irAE onset, the elderly cohort had double the irAE cases that required a transition to best supportive care (BSC) (11.3% vs. 22.4%, p = 0.026). In conclusion, although irAE prevalence remains consistent regardless of age, the increased conversion to BSC post-irAE onset in older adults suggests diminished tolerability and the potential absence of favorable prognosis associated with irAEs in this population. Full article
(This article belongs to the Special Issue Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors)
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14 pages, 878 KiB  
Article
The Vanishing Clinical Value of PD-L1 Status as a Predictive Biomarker in the First-Line Treatment of Urothelial Carcinoma of the Bladder
by Alexander Tamalunas, Can Aydogdu, Lena M. Unterrainer, Melanie Schott, Severin Rodler, Stephan Ledderose, Gerald B. Schulz, Christian G. Stief and Jozefina Casuscelli
Cancers 2024, 16(8), 1536; https://doi.org/10.3390/cancers16081536 - 17 Apr 2024
Cited by 1 | Viewed by 1072
Abstract
Background: Our study endeavors to elucidate the clinical implications of PD-L1 positivity in individuals afflicted with advanced urothelial carcinoma of the bladder (UCB). Methods: Patients with advanced UCB were prospectively enrolled following a radical cystectomy (RC) performed within January 2017 to December 2022 [...] Read more.
Background: Our study endeavors to elucidate the clinical implications of PD-L1 positivity in individuals afflicted with advanced urothelial carcinoma of the bladder (UCB). Methods: Patients with advanced UCB were prospectively enrolled following a radical cystectomy (RC) performed within January 2017 to December 2022 at our tertiary referral center. The clinical outcome, defined as the progression-free survival (PFS) and overall survival (OS) on systemic treatment, was analyzed using an χ2-test, Mann–Whitney U-test, the Kaplan–Meier method, and a log-rank test. Results: A total of 648 patients were included following an RC performed within January 2017 to December 2022. Their PD-L1 status was analyzed with the primary PD-L1-specific antibody (clone SP263, Ventana) and defined both by the CPS and IC-score in 282 patients (43.5%) with a high risk (pT3–pT4 and/or lymph node involvement) or metastatic UCB. While the median PFS was significantly prolonged 5-fold in PD-L1+ patients, we found no difference in OS, regardless of PD-L1 status, or treatment regimen. Conclusions: While PD-L1 positivity indicates prolonged PFS, the presence of PD-L1 does not influence OS rates, suggesting its limited usefulness as a prognostic biomarker in bladder cancer. However, the positive correlation between an PD-L1 status and a sustained response to ICI treatments indicates its potential role as a predictive biomarker. Further research is required to understand how the predictive value of PD-L1 positivity may extend to the use of ICIs in combination with antibody-drug conjugates. Full article
(This article belongs to the Special Issue Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors)
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20 pages, 2175 KiB  
Article
Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types
by Karama Asleh and Rodney J. Ouellette
Cancers 2024, 16(4), 732; https://doi.org/10.3390/cancers16040732 - 9 Feb 2024
Viewed by 1755
Abstract
Immune checkpoint blockade (ICB) benefits only a subset of advanced cancer patients, and predictive biomarkers for immunotherapy response are needed. Recently, copy number alteration (CNA) burden has been proposed to predict ICB resistance. We assessed this finding using the publicly accessible data for [...] Read more.
Immune checkpoint blockade (ICB) benefits only a subset of advanced cancer patients, and predictive biomarkers for immunotherapy response are needed. Recently, copy number alteration (CNA) burden has been proposed to predict ICB resistance. We assessed this finding using the publicly accessible data for 1661 ICB-treated patients whose tumors were profiled by MSK-IMPACT, an approved targeted assay in clinical care. We tested the hypothesis that the continuous increase in CNA burden is associated with poor overall survival following ICB. In addition, we hypothesized that the combinatorial biomarkers of tumor mutational burden (TMB) and CNA burden would better stratify patients for immune status and ICB response. Of the 1661 cases, 79% (n = 1307) were treated with anti PD-1/PD-L1 and the remaining 21% (n = 354) with anti CTLA-4 or the combination of both. In a multivariate analysis, increase in CNA burden was associated with poor overall survival [HR = 1.52, 95% CI (1.01–2.30), p = 0.04]. The combination of biomarkers TMB and CNA burden stratified patients into four clinically distinct subsets among which “LowTMB/HighCNA” showed the worst survival (p < 0.0001). The four patient subsets had unique CNA profiles and enriched pathways, which could predict transcriptional and phenotypic effects related to immune signaling and CD8+ T-cell abundance in the tumor microenvironment. CNA burden was associated with poor overall survival in patients receiving ICB and could improve patient stratification when incorporated with TMB. These findings may guide patient selection for immunotherapy or alternative strategies. Full article
(This article belongs to the Special Issue Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors)
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Review

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20 pages, 2116 KiB  
Review
Soluble CD26: From Suggested Biomarker for Cancer Diagnosis to Plausible Marker for Dynamic Monitoring of Immunotherapy
by Martin Kotrulev, Iria Gomez-Touriño and Oscar J. Cordero
Cancers 2024, 16(13), 2427; https://doi.org/10.3390/cancers16132427 - 30 Jun 2024
Viewed by 1065
Abstract
Soluble CD26 (sCD26), a glycoprotein with dipeptidyl peptidase (DPP4) enzymatic activity, can contribute to early diagnosis of colorectal cancer and advanced adenomas and has been studied, including for prognostic purposes, across various other types of cancer and disease. The latest research in this [...] Read more.
Soluble CD26 (sCD26), a glycoprotein with dipeptidyl peptidase (DPP4) enzymatic activity, can contribute to early diagnosis of colorectal cancer and advanced adenomas and has been studied, including for prognostic purposes, across various other types of cancer and disease. The latest research in this field has confirmed that most, though not all, serum/plasma sCD26 is related to inflammation. The shedding and/or secretion of sCD26 from different immune cells are being investigated, and blood DPP4 activity levels do not correlate very strongly with protein titers. Some of the main substrates of this enzyme are key chemokines involved in immune cell migration, and both soluble and cell-surface CD26 can bind adenosine deaminase (ADA), an enzyme involved in the metabolism of immunosuppressor extracellular adenosine. Of note, there are T cells enriched in CD26 expression and, in mice tumor models, tumor infiltrating lymphocytes exhibited heightened percentages of CD26+ correlating with tumor regression. We employed sCD26 as a biomarker in the follow-up after curative resection of colorectal cancer for the early detection of tumor recurrence. Changes after treatment with different biological disease-modifying antirheumatic drugs, including Ig-CTLA4, were also observed in rheumatoid arthritis. Serum soluble CD26/DPP4 titer variation has recently been proposed as a potential prognostic biomarker after a phase I trial in cancer immunotherapy with a humanized anti-CD26 antibody. We propose that dynamic monitoring of sCD26/DPP4 changes, in addition to well-known inflammatory biomarkers such as CRP already in use as informative for immune checkpoint immunotherapy, may indicate resistance or response during the successive steps of the treatment. As tumor cells expressing CD26 can also produce sCD26, the possibility of sorting immune- from non-immune-system-originated sCD26 is discussed. Full article
(This article belongs to the Special Issue Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors)
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14 pages, 835 KiB  
Review
MIF and CD74 as Emerging Biomarkers for Immune Checkpoint Blockade Therapy
by Rosalyn M. Fey, Rebecca A. Nichols, Thuy T. Tran, Arthur A. Vandenbark and Rajan P. Kulkarni
Cancers 2024, 16(9), 1773; https://doi.org/10.3390/cancers16091773 - 4 May 2024
Viewed by 1765
Abstract
Immune checkpoint blockade (ICB) therapy is used to treat a wide range of cancers; however, some patients are at risk of developing treatment resistance and/or immune-related adverse events (irAEs). Thus, there is a great need for the identification of reliable predictive biomarkers for [...] Read more.
Immune checkpoint blockade (ICB) therapy is used to treat a wide range of cancers; however, some patients are at risk of developing treatment resistance and/or immune-related adverse events (irAEs). Thus, there is a great need for the identification of reliable predictive biomarkers for response and toxicity. The cytokine MIF (macrophage migration inhibitory factor) and its cognate receptor CD74 are intimately connected with cancer progression and have previously been proposed as prognostic biomarkers for patient outcome in various cancers, including solid tumors such as malignant melanoma. Here, we assess their potential as predictive biomarkers for response to ICB therapy and irAE development. We provide a brief overview of their function and roles in the context of cancer and autoimmune disease. We also review the evidence showing that MIF and CD74 may be of use as predictive biomarkers of patient response to ICB therapy and irAE development. We also highlight that careful consideration is required when assessing the potential of serum MIF levels as a biomarker due to its reported circadian expression in human plasma. Finally, we suggest future directions for the establishment of MIF and CD74 as predictive biomarkers for ICB therapy and irAE development to guide further research in this field. Full article
(This article belongs to the Special Issue Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors)
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23 pages, 2838 KiB  
Review
Coagulation Protease-Driven Cancer Immune Evasion: Potential Targets for Cancer Immunotherapy
by Subhojit Paul, Tanmoy Mukherjee and Kaushik Das
Cancers 2024, 16(8), 1568; https://doi.org/10.3390/cancers16081568 - 19 Apr 2024
Viewed by 1050
Abstract
Blood coagulation and cancer are intrinsically connected, hypercoagulation-associated thrombotic complications are commonly observed in certain types of cancer, often leading to decreased survival in cancer patients. Apart from the common role in coagulation, coagulation proteases often trigger intracellular signaling in various cancers via [...] Read more.
Blood coagulation and cancer are intrinsically connected, hypercoagulation-associated thrombotic complications are commonly observed in certain types of cancer, often leading to decreased survival in cancer patients. Apart from the common role in coagulation, coagulation proteases often trigger intracellular signaling in various cancers via the activation of a G protein-coupled receptor superfamily protease: protease-activated receptors (PARs). Although the role of PARs is well-established in the development and progression of certain types of cancer, their impact on cancer immune response is only just emerging. The present review highlights how coagulation protease-driven PAR signaling plays a key role in modulating innate and adaptive immune responses. This is followed by a detailed discussion on the contribution of coagulation protease-induced signaling in cancer immune evasion, thereby supporting the growth and development of certain tumors. A special section of the review demonstrates the role of coagulation proteases, thrombin, factor VIIa, and factor Xa in cancer immune evasion. Targeting coagulation protease-induced signaling might be a potential therapeutic strategy to boost the immune surveillance mechanism of a host fighting against cancer, thereby augmenting the clinical consequences of targeted immunotherapeutic regimens. Full article
(This article belongs to the Special Issue Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors)
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