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Targeting Immune Checkpoints for Cancer Therapy: Potential and Challenges

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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 3860

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Special Issue Editors

Dr. Mona Kamal Saadeldin

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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

Dr. Nicolò Eleonora

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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

Dr. Amal Kamal Abdel-Aziz

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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

Dr. D’Amico Paolo

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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

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 short 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

immune checkpoint inhibitors
biomarkers
resistance
toxicity
cancer
drug discovery
therapeutic regimens

Published Papers (4 papers)

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Research

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20 pages, 1410 KiB

Open AccessArticle

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 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

(This article belongs to the Special Issue Targeting Immune Checkpoints for Cancer Therapy: Potential and Challenges)

34 pages, 12112 KiB

Open AccessArticle

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 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

(This article belongs to the Special Issue Targeting Immune Checkpoints for Cancer Therapy: Potential and Challenges)

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Review

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17 pages, 558 KiB

Open AccessReview

Checkpoint Inhibitors in Dogs: Are We There Yet?

by Antonio Giuliano, Pedro A. B. Pimentel and Rodrigo S. Horta

Cancers 2024, 16(11), 2003; https://doi.org/10.3390/cancers16112003 - 24 May 2024

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Abstract

Immune checkpoint inhibitors (ICI) have revolutionised cancer treatment in people. Immune checkpoints are important regulators of the body’s reaction to immunological stimuli. The most studied immune checkpoint molecules are programmed death (PD-1) with its ligand (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) with its ligands CD80 (B7-1) and CD86 (B7-2). Certain tumours can evade immunosurveillance by activating these immunological checkpoint targets. These proteins are often upregulated in cancer cells and tumour-infiltrating lymphocytes, allowing cancer cells to evade immune surveillance and promote tumour growth. By blocking inhibitory checkpoints, ICI can help restore the immune system to effectively fight cancer. Several studies have investigated the expression of these and other immune checkpoints in human cancers and have shown their potential as therapeutic targets. In recent years, there has been growing interest in studying the expression of immune checkpoints in dogs with cancer, and a few small clinical trials with ICI have already been performed on these species. Emerging studies in veterinary oncology are centred around developing and validating canine-targeted antibodies. Among ICIs, anti-PD-1 and anti-PD-L1 treatments stand out as the most promising, mirroring the success in human medicine over the past decade. Nevertheless, the efficacy of caninized antibodies remains suboptimal, especially for canine oral melanoma. To enhance the utilisation of ICIs, the identification of predictive biomarkers for treatment response and the thorough screening of individual tumours are crucial. Such endeavours hold promise for advancing personalised medicine within veterinary practice, thereby improving treatment outcomes. This article aims to review the current research literature about the expression of immune checkpoints in canine cancer and the current results of ICI treatment in dogs. Full article

(This article belongs to the Special Issue Targeting Immune Checkpoints for Cancer Therapy: Potential and Challenges)

20 pages, 1271 KiB

Open AccessReview

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

Viewed by 1854

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, 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

(This article belongs to the Special Issue Targeting Immune Checkpoints for Cancer Therapy: Potential and Challenges)

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