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Immune Checkpoint Inhibitors and Immune Checkpoint Resistance

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 17466

Special Issue Editor

Division of Experimental Therapeutics, Istituto Europeo di Oncologia, Milano, Italy
Interests: breast cancer; endocrine therapy resistance; immunotherapy; immunocheckpoint inhibitors; immunocheckpoint resistance; cardiotoxicity/cardioncology; notch inhibitors

Special Issue Information

Dear Colleagues,

The immuno-oncology era (IO) has achieved many successes and represents an important milestone for cancer treatment. Immune checkpoints are important regulators of immune activation, and they play a key role in maintaining immune balance and preventing autoimmune diseases. Therefore, immune checkpoint inhibitors (ICIs) have led to a revolution in the management of many tumor types, such as melanoma, non-small cell lung cancer (NSCLC), kidney cancer, and bladder/urothelial cancer. Starting with the approval of anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) for advanced-stage melanoma in 2011, other antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) quickly gained US Food and Drug Administration (FDA) approval for the treatment of a wide array of cancer types, demonstrating a statistically significant increase in overall survival. Considering the remarkable efficacy of IO in clinical trials, the FDA has approved a variety of immune checkpoint inhibitors for the treatment of advanced tumors, first as monotherapy, and later in combination. In clinical research, the number of IO targets in development has risen from 265 in 2017 to 469 in 2019 (“Clinical Challenges of Immune Checkpoint Inhibitors”. Maria de Miguel and Emialiano Calvo, Cancer Cell https://0-doi-org.brum.beds.ac.uk/10.1016/j.ccell.2020.07.004).

In addition to the abovementioned classical immune checkpoints (anti-CTL4, anti-PD1, anti-PD-L1), a number of immune checkpoint pathways have been discovered with different mechanisms of action, such as LAG 3 and T cell immunoglobulin mucin 3 (Tim-3). The inhibition of both LAG 3 and PD-1 can reverse the depletion of lymphocytes, thereby enhancing the immune response, while the blockade of Tim-3 can enhance the antitumor effect of PD-1 inhibitors.

However, despite the success of ICIs, resistance to these agents restricts the number of patients able to achieve durable responses, and immune-related adverse events can complicate treatment. Thus, a better understanding of the requirements for an effective and safe antitumor immune response following ICI therapy is needed. Studies of both tumoral and systemic changes in the immune system following ICI therapy have yielded insight into the basis for both efficacy and resistance. The understanding of the mechanisms of resistance to ICIs represents an important area of investigation in order to be able to combine ICIs with other agents or design new immunotherapies.

Dr. Marzia Adelia Locatelli
Guest Editor

Manuscript Submission Information

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Keywords

  • immune checkpoint inhibitors
  • anti-PD-1
  • anti-PD-L1
  • immune checkpoint resistance
  • anti-LAG3
  • anti-TIM-3
  • primary resistance
  • acquired resistance
  • immune-related adverse events
  • biomarkers
  • immunotherapy
  • synergistic effect
  • PD-1/PD-L1 setting
  • tumor microenvironment

Published Papers (5 papers)

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Research

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17 pages, 1660 KiB  
Article
Inappropriate Expression of PD-1 and CTLA-4 Checkpoints in Myeloma Patients Is More Pronounced at Diagnosis: Implications for Time to Progression and Response to Therapeutic Checkpoint Inhibitors
by Anna Kulikowska de Nałęcz, Lidia Ciszak, Lidia Usnarska-Zubkiewicz, Edyta Pawlak, Irena Frydecka, Magdalena Szmyrka and Agata Kosmaczewska
Int. J. Mol. Sci. 2023, 24(6), 5730; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065730 - 17 Mar 2023
Cited by 2 | Viewed by 1369
Abstract
Multiple myeloma (MM) is a hematologic malignancy characterized by severely profound immune dysfunction. Therefore, the efficacy of drugs targeting the immune environments, such as immune checkpoint inhibitors (ICIs), is of high clinical importance. However, several clinical trials evaluating ICIs in MM in different [...] Read more.
Multiple myeloma (MM) is a hematologic malignancy characterized by severely profound immune dysfunction. Therefore, the efficacy of drugs targeting the immune environments, such as immune checkpoint inhibitors (ICIs), is of high clinical importance. However, several clinical trials evaluating ICIs in MM in different therapeutic combinations revealed underwhelming results showing a lack of clinical efficacy and excessive side effects. The underlying mechanisms of resistance to ICIs observed in the majority of MM patients are still under investigation. Recently, we demonstrated that inappropriate expression of PD-1 and CTLA-4 on CD4 T cells in active MM is associated with adverse clinical outcomes and treatment status. The aim of the current study was to determine the usefulness of immune checkpoint expression assessment as a predictive biomarker of the response to therapeutic inhibitors. For this purpose, along with checkpoint expression estimated by flow cytometry, we evaluated the time to progression (TTP) of MM patients at different clinical stages (disease diagnosis and relapse) depending on the checkpoint expression level; the cut-off point (dividing patients into low and high expressors) was selected based on the median value. Herein, we confirmed the defective levels of regulatory PD-1, CTLA-4 receptors, and the CD69 marker activation in newly diagnosed (ND) patients, whereas relapsed/refractory patients (RR) exhibited their recovered values and reactivity. Additionally, substantially higher populations of senescent CD4+CD28 T cells were found in MM, primarily in NDMM subjects. These observations suggest the existence of two dysfunctional states in MM CD4 T cells with the predominance of immunosenescence at disease diagnosis and exhaustion at relapse, thus implying different responsiveness to the external receptor blockade depending on the disease stage. Furthermore, we found that lower CTLA-4 levels in NDMM patients or higher PD-1 expression in RRMM patients may predict early relapse. In conclusion, our study clearly showed that the checkpoint level in CD4 T cells may significantly affect the time to MM progression concerning the treatment status. Therefore, when considering novel therapies and potent combinations, it should be taken into account that blocking PD-1 rather than CTLA-4 might be a beneficial form of immunotherapy for only a proportion of RRMM patients. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitors and Immune Checkpoint Resistance)
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20 pages, 4174 KiB  
Article
A New Signature That Predicts Progression-Free Survival of Clear Cell Renal Cell Carcinoma with Anti-PD-1 Therapy
by Jingwei Lin, Yingxin Cai, Yuxiang Ma, Jinyou Pan, Zuomin Wang, Jianpeng Zhang, Yangzhou Liu and Zhigang Zhao
Int. J. Mol. Sci. 2023, 24(6), 5332; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065332 - 10 Mar 2023
Cited by 2 | Viewed by 1854
Abstract
Immunotherapy has greatly improved the survival time and quality of life of patients with renal cell carcinoma, but the benefits are limited to a small portion of patients. There are too few new biomarkers that can be used to identify molecular subtypes of [...] Read more.
Immunotherapy has greatly improved the survival time and quality of life of patients with renal cell carcinoma, but the benefits are limited to a small portion of patients. There are too few new biomarkers that can be used to identify molecular subtypes of renal clear cell carcinoma and predict survival time with anti-PD-1 treatment. Single-cell RNA data of clear cell renal cell carcinoma (ccRCC) treated with anti-PD-1 were obtained from public databases, then 27,707 high-quality CD4 + T and CD8 + T cells were obtained for subsequent analysis. Firstly, genes set variation analysis and CellChat algorithm were used to explore potential molecular pathway differences and intercellular communication between the responder and non-responder groups. Additionally, differentially expressed genes (DEGs) between the responder and non-responder groups were obtained using the “edgeR” package, and ccRCC samples from TCGA-KIRC (n = 533) and ICGA-KIRC (n = 91) were analyzed by the unsupervised clustering algorithm to recognize molecular subtypes with different immune characteristics. Finally, using univariate Cox analysis, least absolute shrinkage and selection operator (Lasso) regression, and multivariate Cox regression, the prognosis model of immunotherapy was established and verified to predict the progression-free survival of ccRCC patients treated with anti-PD-1. At the single cell level, there are different signal pathways and cell communication between the immunotherapy responder and non-responder groups. In addition, our research also confirms that the expression level of PDCD1/PD-1 is not an effective marker for predicting the response to immune checkpoint inhibitors (ICIs). The new prognostic immune signature (PIS) enabled the classification of ccRCC patients with anti-PD-1 therapy into high- and low-risk groups, and the progression-free survival times (PFS) and immunotherapy responses were significantly different between these two groups. In the training group, the area under the ROC curve (AUC) for predicting 1-, 2- and 3-year progression-free survival was 0.940 (95% CI: 0.894–0.985), 0.981 (95% CI: 0.960–1.000), and 0.969 (95% CI: 0.937–1.000), respectively. Validation sets confirm the robustness of the signature. This study revealed the heterogeneity between the anti-PD-1 responder and non-responder groups from different angles and established a robust PIS to predict the progression-free survival of ccRCC patients receiving immune checkpoint inhibitors. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitors and Immune Checkpoint Resistance)
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Review

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18 pages, 1348 KiB  
Review
Rheumatic Immune-Related Adverse Events due to Immune Checkpoint Inhibitors—A 2023 Update
by Quang Minh Dang, Ryu Watanabe, Mayu Shiomi, Kazuo Fukumoto, Tomomi W. Nobashi, Tadashi Okano, Shinsuke Yamada and Motomu Hashimoto
Int. J. Mol. Sci. 2023, 24(6), 5643; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065643 - 15 Mar 2023
Cited by 8 | Viewed by 3528
Abstract
With the aging of the population, malignancies are becoming common complications in patients with rheumatoid arthritis (RA), particularly in elderly patients. Such malignancies often interfere with RA treatment. Among several therapeutic agents, immune checkpoint inhibitors (ICIs) which antagonize immunological brakes on T lymphocytes [...] Read more.
With the aging of the population, malignancies are becoming common complications in patients with rheumatoid arthritis (RA), particularly in elderly patients. Such malignancies often interfere with RA treatment. Among several therapeutic agents, immune checkpoint inhibitors (ICIs) which antagonize immunological brakes on T lymphocytes have emerged as a promising treatment option for a variety of malignancies. In parallel, evidence has accumulated that ICIs are associated with numerous immune-related adverse events (irAEs), such as hypophysitis, myocarditis, pneumonitis, and colitis. Moreover, ICIs not only exacerbate pre-existing autoimmune diseases, but also cause de novo rheumatic disease–like symptoms, such as arthritis, myositis, and vasculitis, which are currently termed rheumatic irAEs. Rheumatic irAEs differ from classical rheumatic diseases in multiple aspects, and treatment should be individualized based on the severity. Close collaboration with oncologists is critical for preventing irreversible organ damage. This review summarizes the current evidence regarding the mechanisms and management of rheumatic irAEs with focus on arthritis, myositis, and vasculitis. Based on these findings, potential therapeutic strategies against rheumatic irAEs are discussed. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitors and Immune Checkpoint Resistance)
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25 pages, 994 KiB  
Review
Mouse Models for Immune Checkpoint Blockade Therapeutic Research in Oral Cancer
by Wei-Chiao Chiu, Da-Liang Ou and Ching-Ting Tan
Int. J. Mol. Sci. 2022, 23(16), 9195; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169195 - 16 Aug 2022
Cited by 6 | Viewed by 5553
Abstract
The most prevalent oral cancer globally is oral squamous cell carcinoma (OSCC). The invasion of adjacent bones and the metastasis to regional lymph nodes often lead to poor prognoses and shortened survival times in patients with OSCC. Encouraging immunotherapeutic responses have been seen [...] Read more.
The most prevalent oral cancer globally is oral squamous cell carcinoma (OSCC). The invasion of adjacent bones and the metastasis to regional lymph nodes often lead to poor prognoses and shortened survival times in patients with OSCC. Encouraging immunotherapeutic responses have been seen with immune checkpoint inhibitors (ICIs); however, these positive responses to monotherapy have been limited to a small subset of patients. Therefore, it is urgent that further investigations into optimizing immunotherapies are conducted. Areas of research include identifying novel immune checkpoints and targets and tailoring treatment programs to meet the needs of individual patients. Furthermore, the advancement of combination therapies against OSCC is also critical. Thus, additional studies are needed to ensure clinical trials are successful. Mice models are advantageous in immunotherapy research with several advantages, such as relatively low costs and high tumor growth success rate. This review paper divided methods for establishing OSCC mouse models into four categories: syngeneic tumor models, chemical carcinogen induction, genetically engineered mouse, and humanized mouse. Each method has advantages and disadvantages that influence its application in OSCC research. This review comprehensively surveys the literature and summarizes the current mouse models used in immunotherapy, their advantages and disadvantages, and details relating to the cell lines for oral cancer growth. This review aims to present evidence and considerations for choosing a suitable model establishment method to investigate the early diagnosis, clinical treatment, and related pathogenesis of OSCC. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitors and Immune Checkpoint Resistance)
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17 pages, 582 KiB  
Review
Challenges of the Immunotherapy: Perspectives and Limitations of the Immune Checkpoint Inhibitor Treatment
by Paula Dobosz, Maria Stępień, Anna Golke and Tomasz Dzieciątkowski
Int. J. Mol. Sci. 2022, 23(5), 2847; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052847 - 05 Mar 2022
Cited by 17 | Viewed by 4325
Abstract
Immunotherapy is a quickly developing type of treatment and the future of therapy in oncology. This paper is a review of recent findings in the field of immunotherapy with an emphasis on immune checkpoint inhibitors. The challenges that immunotherapy might face in near [...] Read more.
Immunotherapy is a quickly developing type of treatment and the future of therapy in oncology. This paper is a review of recent findings in the field of immunotherapy with an emphasis on immune checkpoint inhibitors. The challenges that immunotherapy might face in near future, such as primary and acquired resistance and the irAEs, are described in this article, as well as the perspectives such as identification of environmental modifiers of immunity and development of anti-cancer vaccines and combined therapies. There are multiple factors that may be responsible for immunoresistance, such as genomic factors, factors related to the immune system cells or to the cancer microenvironment, factors emerging from the host cells, as well as other factors such as advanced age, biological sex, diet, many hormones, existing comorbidities, and the gut microbiome. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitors and Immune Checkpoint Resistance)
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