Targeting Immune Checkpoints for Cancer Therapy: Potential and Challenges

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

Deadline for manuscript submissions: 15 August 2024 | Viewed by 3424

Special Issue Editors


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Guest Editor
Department of Electrical Engineering and Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
Interests: immunotherapy; cancer resistance; biomarker; drug discovery

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Guest Editor
1. Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
2. Department of Oncology and Haematology (DIPO), University of Milan, Milan, Italy
3. Weill Cornell Medicine, New York, NY, USA
Interests: personalized medicine; cancer immunotherapy; drug development; liquid biopsy; breast cancer

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Guest Editor
Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy
Interests: cancer resistance; toxicity; drug discovery; immunotherapy; biomarker

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Guest Editor
Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Interests: immunotherapy; cancer; breast cancer; liquid biopsy; clinical trials; drug development

Special Issue Information

Dear Colleagues,

Immune checkpoint inhibitors (ICIs) are thought to have revolutionized cancer therapy. However, their clinical efficacy/potential is largely hampered by the emergence of cancer resistance and ICI-associated toxicities. The areas of interest of this Special Issue include:

  • The identification and validation of novel druggable immune checkpoints;
  • The systematic deciphering of the molecular mechanisms underlying intrinsic as well as acquired cancer resistance and toxicity to immune checkpoint inhibitors;
  • Novel biomarkers for patient selection and monitoring drug response;
  • Innovative, effective and tolerable therapeutic strategies exploiting the vulnerabilities induced in the resistant cancer subpopulation as well as exhausted immune cells to ultimately trigger synthetic lethality;
  • Literature revisions of the most recent clinical achievements, with a critical appraisal of new opportunities and upcoming challenges in the field.

This Special Issue of Cancers therefore welcomes new basic, translational and clinical research articles and timely reviews regarding all aspects of the potential and challenges of using immune checkpoint inhibitors in cancer therapy.

Dr. Mona Kamal Saadeldin
Dr. Nicolò Eleonora
Dr. Amal Kamal Abdel-Aziz
Dr. D’Amico Paolo
Guest Editors

Manuscript Submission Information

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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

  • immune checkpoint inhibitors
  • biomarkers
  • resistance
  • toxicity
  • cancer
  • drug discovery
  • therapeutic regimens

Published Papers (3 papers)

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Research

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20 pages, 1410 KiB  
Article
GAS-Luc2 Reporter Cell Lines for Immune Checkpoint Drug Screening in Solid Tumors
by Hyeyoun Chang, John G. Foulke, Luping Chen, Fang Tian and Zhizhan Gu
Cancers 2024, 16(11), 1965; https://doi.org/10.3390/cancers16111965 - 22 May 2024
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Abstract
Recent studies highlight the integral role of the interferon gamma receptor (IFNγR) pathway in T cell–mediated cytotoxicity against solid but not liquid tumors. IFNγ not only directly facilitates tumor cell death by T cells but also indirectly promotes cytotoxicity via myeloid phagocytosis in [...] Read more.
Recent studies highlight the integral role of the interferon gamma receptor (IFNγR) pathway in T cell–mediated cytotoxicity against solid but not liquid tumors. IFNγ not only directly facilitates tumor cell death by T cells but also indirectly promotes cytotoxicity via myeloid phagocytosis in the tumor microenvironment. Meanwhile, full human ex vivo immune checkpoint drug screening remains challenging. We hypothesized that an engineered gamma interferon activation site response element luciferase reporter (GAS-Luc2) can be utilized for immune checkpoint drug screening in diverse ex vivo T cell–solid tumor cell co-culture systems. We comprehensively profiled cell surface proteins in ATCC’s extensive collection of human tumor and immune cell lines, identifying those with endogenously high expression of established and novel immune checkpoint molecules and binding ligands. We then engineered three GAS-Luc2 reporter tumor cell lines expressing immune checkpoints PD-L1, CD155, or B7-H3/CD276. Luciferase expression was suppressed upon relevant immune checkpoint–ligand engagement. In the presence of an immune checkpoint inhibitor, T cells released IFNγ, activating the JAK-STAT pathway in GAS-Luc2 cells, and generating a quantifiable bioluminescent signal for inhibitor evaluation. These reporter lines also detected paracrine IFNγ signaling for immune checkpoint-targeted ADCC drug screening. Further development into an artificial antigen-presenting cell line (aAPC) significantly enhanced T cell signaling for superior performance in these ex vivo immune checkpoint drug screening platforms. Full article
34 pages, 12112 KiB  
Article
Exploring the Significance of Immune Checkpoints and EBV Reactivation in Antibody Deficiencies with Near-Normal Immunoglobulin Levels or Hyperimmunoglobulinemia
by Paulina Mertowska, Sebastian Mertowski, Konrad Smolak, Marcin Pasiarski, Jolanta Smok-Kalwat, Stanisław Góźdź and Ewelina Grywalska
Cancers 2023, 15(20), 5059; https://doi.org/10.3390/cancers15205059 - 19 Oct 2023
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Abstract
This study delves into the intricate landscape of primary immunodeficiencies, with a particular focus on antibody deficiencies characterized by near-normal immunoglobulin levels or hyperimmunoglobulinemia. Contrary to the conventional focus on genetic dysregulation, these studies investigate the key roles of immune checkpoints, such as [...] Read more.
This study delves into the intricate landscape of primary immunodeficiencies, with a particular focus on antibody deficiencies characterized by near-normal immunoglobulin levels or hyperimmunoglobulinemia. Contrary to the conventional focus on genetic dysregulation, these studies investigate the key roles of immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, on selected subpopulations of T and B lymphocytes and their serum concentrations of soluble forms in patients recruited for the studies in healthy volunteers. In addition, the studies also show the role of Epstein–Barr virus (EBV) reactivation and interactions with tested pathways of immune checkpoints involved in the immunopathogenesis of this disease. By examining the context of antibody deficiencies, this study sheds light on the nuanced interplay of factors beyond genetics, particularly the immune dysregulations that occur in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical presentation of patients and may contribute to the development of cancer in the future, especially related to hematological malignancies. Full article
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Review

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20 pages, 1271 KiB  
Review
Beyond PD(L)-1 Blockade in Microsatellite-Instable Cancers: Current Landscape of Immune Co-Inhibitory Receptor Targeting
by Edoardo Crimini, Luca Boscolo Bielo, Pier Paolo Maria Berton Giachetti, Gloria Pellizzari, Gabriele Antonarelli, Beatrice Taurelli Salimbeni, Matteo Repetto, Carmen Belli and Giuseppe Curigliano
Cancers 2024, 16(2), 281; https://doi.org/10.3390/cancers16020281 - 9 Jan 2024
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Abstract
High microsatellite instability (MSI-H) derives from genomic hypermutability due to deficient mismatch repair function. Colorectal (CRC) and endometrial cancers (EC) are the tumor types that more often present MSI-H. Anti-PD(L)-1 antibodies have been demonstrated to be agnostically effective in patients with MSI-H cancer, [...] Read more.
High microsatellite instability (MSI-H) derives from genomic hypermutability due to deficient mismatch repair function. Colorectal (CRC) and endometrial cancers (EC) are the tumor types that more often present MSI-H. Anti-PD(L)-1 antibodies have been demonstrated to be agnostically effective in patients with MSI-H cancer, but 50–60% of them do not respond to single-agent treatment, highlighting the necessity of expanding their treatment opportunities. Ipilimumab (anti-CTLA4) is the only immune checkpoint inhibitor (ICI) non-targeting PD(L)-1 that has been approved so far by the FDA for MSI-H cancer, namely, CRC in combination with nivolumab. Anti-TIM3 antibody LY3321367 showed interesting clinical activity in combination with anti-PDL-1 antibody in patients with MSI-H cancer not previously treated with anti-PD(L)-1. In contrast, no clinical evidence is available for anti-LAG3, anti-TIGIT, anti-BTLA, anti-ICOS and anti-IDO1 antibodies in MSI-H cancers, but clinical trials are ongoing. Other immunotherapeutic strategies under study for MSI-H cancers include vaccines, systemic immunomodulators, STING agonists, PKM2 activators, T-cell immunotherapy, LAIR-1 immunosuppression reversal, IL5 superagonists, oncolytic viruses and IL12 partial agonists. In conclusion, several combination therapies of ICIs and novel strategies are emerging and may revolutionize the treatment paradigm of MSI-H patients in the future. A huge effort will be necessary to find reliable immune biomarkers to personalize therapeutical decisions. Full article
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