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Cancers
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Checkpoint Markers and Cancer Microenvironment: What Do We Know?
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Checkpoint Markers and Cancer Microenvironment: What Do We Know?

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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 13871

Special Issue Editor

Prof. Dr. Vasso Apostolopoulos

E-Mail Website
Guest Editor
Institute for Health and Sport, Victoria University, Melbourne, VIC 3011, Australia
Interests: immunology; protein crystallography; medicinal chemistry; cellular and molecular biology; extensive translational research; clinical trials; vaccines; drugs; healthy ageing; chronic diseases; inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Inhibitory checkpoint molecules are targets for cancer immunotherapy due to their potential for use in multiple types of cancer. Immune checkpoint blockade has vastly changed the landscape of cancer treatment and has shown a promising prognosis for cancer patients. However, the majority of patients will not benefit from immune checkpoint inhibitor therapy (innate resistance), and a substantial proportion of the responding patients will progress while on treatment (acquired resistance). Therefore, it is essential to investigate biomarkers to predict the efficacy of immune checkpoint inhibitors. In this Special Issue, we hope to collect papers on checkpoint markers for different cancers. We hope that this will promote study in this field.

Prof. Dr. Vasso Apostolopoulos
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 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

  • inhibitory checkpoint
  • immune checkpoint
  • tumor necrosis factor (TNF) receptor superfamily

Published Papers (5 papers)

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Editorial

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6 pages, 679 KiB  
Editorial
Checkpoint Markers and Tumor Microenvironment: What Do We Know?
by Ramya Ephraim, Sarah Fraser, Kulmira Nurgali and Vasso Apostolopoulos
Cancers 2022, 14(15), 3788; https://doi.org/10.3390/cancers14153788 - 04 Aug 2022
Cited by 9 | Viewed by 1980
Abstract
The cancer microenvironment, or tumor microenvironment (TME), describes the non-cancerous cells present in the tumor, such as fibroblasts, immune cells, and cells that comprise the blood vessels and proteins produced by all of the cells present in the tumor that support the growth [...] Read more.
The cancer microenvironment, or tumor microenvironment (TME), describes the non-cancerous cells present in the tumor, such as fibroblasts, immune cells, and cells that comprise the blood vessels and proteins produced by all of the cells present in the tumor that support the growth of the cancer cells [...] Full article
(This article belongs to the Special Issue Checkpoint Markers and Cancer Microenvironment: What Do We Know?)
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Research

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19 pages, 3247 KiB  
Article
Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion
by Christina Bruss, Kerstin Kellner, Veruschka Albert, James A. Hutchinson, Stephan Seitz, Olaf Ortmann, Gero Brockhoff and Anja K. Wege
Cancers 2023, 15(9), 2615; https://doi.org/10.3390/cancers15092615 - 04 May 2023
Cited by 1 | Viewed by 2180
Abstract
Checkpoint blockade is particularly based on PD-1/PD-L1-inhibiting antibodies. However, an efficient immunological tumor defense can be blocked not only by PD-(L)1 but also by the presence of additional immune checkpoint molecules. Here, we investigated the co-expression of several immune checkpoint proteins and the [...] Read more.
Checkpoint blockade is particularly based on PD-1/PD-L1-inhibiting antibodies. However, an efficient immunological tumor defense can be blocked not only by PD-(L)1 but also by the presence of additional immune checkpoint molecules. Here, we investigated the co-expression of several immune checkpoint proteins and the soluble forms thereof (e.g., PD-1, TIM-3, LAG-3, PD-L1, PD-L2 and others) in humanized tumor mice (HTM) simultaneously harboring cell line-derived (JIMT-1, MDA-MB-231, MCF-7) or patient-derived breast cancer and a functional human immune system. We identified tumor-infiltrating T cells with a triple-positive PD-1, LAG-3 and TIM-3 phenotype. While PD-1 expression was increased in both the CD4 and CD8 T cells, TIM-3 was found to be upregulated particularly in the cytotoxic T cells in the MDA-MB-231-based HTM model. High levels of soluble TIM-3 and galectin-9 (a TIM-3 ligand) were detected in the serum. Surprisingly, soluble PD-L2, but only low levels of sPD-L1, were found in mice harboring PD-L1-positive tumors. Analysis of a dataset containing 3039 primary breast cancer samples on the R2 Genomics Analysis Platform revealed increased TIM-3, galectin-9 and LAG-3 expression, not only in triple-negative breast cancer but also in the HER2+ and hormone receptor-positive breast cancer subtypes. These data indicate that LAG-3 and TIM-3 represent additional key molecules within the breast cancer anti-immunity landscape. Full article
(This article belongs to the Special Issue Checkpoint Markers and Cancer Microenvironment: What Do We Know?)
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12 pages, 836 KiB  
Article
Development of Monoclonal Antibodies Targeting Canine PD-L1 and PD-1 and Their Clinical Relevance in Canine Apocrine Gland Anal Sac Adenocarcinoma
by Lucia Minoli, Luca Licenziato, Mikolaj Kocikowski, Marzia Cino, Katarzyna Dziubek, Selina Iussich, Antonella Fanelli, Emanuela Morello, Marina Martano, Ted Hupp, Borek Vojtesek, Maciej Parys and Luca Aresu
Cancers 2022, 14(24), 6188; https://doi.org/10.3390/cancers14246188 - 14 Dec 2022
Cited by 4 | Viewed by 2115
Abstract
Canine apocrine gland anal sac adenocarcinoma (AGASACA) is an aggressive canine tumor originating from the anal sac glands. Surgical resection, with or without adjuvant chemotherapy, represents the standard of care for this tumor, but the outcome is generally poor, particularly for tumors diagnosed [...] Read more.
Canine apocrine gland anal sac adenocarcinoma (AGASACA) is an aggressive canine tumor originating from the anal sac glands. Surgical resection, with or without adjuvant chemotherapy, represents the standard of care for this tumor, but the outcome is generally poor, particularly for tumors diagnosed at an advanced stage. For this reason, novel treatment options are warranted, and a few recent reports have suggested the activation of the immune checkpoint axis in canine AGASACA. In our study, we developed canine-specific monoclonal antibodies targeting PD-1 and PD-L1. A total of 41 AGASACAs with complete clinical and follow-up information were then analyzed by immunohistochemistry for the expression of the two checkpoint molecules (PD-L1 and PD-1) and the presence of tumor-infiltrating lymphocytes (CD3 and CD20), which were evaluated within the tumor bulk (intratumor) and in the surrounding stroma (peritumor). Seventeen AGASACAs (42%) expressed PD-L1 in a range between 5% and 95%. The intratumor lymphocytes were predominantly CD3+ T-cells and were positively correlated with the number of PD-1+ intratumor lymphocytes (ρ = 0.36; p = 0.02). The peritumor lymphocytes were a mixture of CD3+ and CD20+ cells with variable PD-1 expression (range 0–50%). PD-L1 expression negatively affected survival only in the subgroup of dogs treated with surgery alone (n = 14; 576 vs. 235 days). The presence of a heterogeneous lymphocytic infiltrate and the expression of PD-1 and PD-L1 molecules support the relevance of the immune microenvironment in canine AGASACAs and the potential value of immune checkpoints as promising therapeutic targets. Full article
(This article belongs to the Special Issue Checkpoint Markers and Cancer Microenvironment: What Do We Know?)
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Review

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23 pages, 1863 KiB  
Review
Configuring Therapeutic Aspects of Immune Checkpoints in Lung Cancer
by Avinash Khadela, Vivek P. Chavda, Humzah Postwala, Ramya Ephraim, Vasso Apostolopoulos and Yesha Shah
Cancers 2023, 15(2), 543; https://doi.org/10.3390/cancers15020543 - 16 Jan 2023
Cited by 8 | Viewed by 2371
Abstract
Immune checkpoints are unique components of the body’s defense mechanism that safeguard the body from immune responses that are potent enough to harm healthy body cells. When proteins present on the surface of T cells recognize and bind to the proteins present on [...] Read more.
Immune checkpoints are unique components of the body’s defense mechanism that safeguard the body from immune responses that are potent enough to harm healthy body cells. When proteins present on the surface of T cells recognize and bind to the proteins present on other tumor cells, immune checkpoints are triggered. These proteins are called immunological checkpoints. The T cells receive an on/off signal when the checkpoints interact with companion proteins. This might avert the host’s immune system from eliminating cancer cells. The standard care plan for the treatment of non-small cell lung cancer (NSCLC) has been revolutionized with the use of drugs targeting immune checkpoints, in particular programmed cell death protein 1. These drugs are now extended for their potential to manage SCLC. However, it is acknowledged that these drugs have specific immune related adverse effects. Herein, we discuss the use of immune checkpoint inhibitors in patients with NSCLC and SCLC, their outcomes, and future perspectives. Full article
(This article belongs to the Special Issue Checkpoint Markers and Cancer Microenvironment: What Do We Know?)
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20 pages, 2742 KiB  
Review
Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors
by Xavier Thuru, Romain Magnez, Hassiba El-Bouazzati, Gérard Vergoten, Bruno Quesnel and Christian Bailly
Cancers 2022, 14(14), 3368; https://doi.org/10.3390/cancers14143368 - 11 Jul 2022
Cited by 7 | Viewed by 4491
Abstract
Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have considerably improved the treatment of some cancers, but novel drugs, new combinations, and treatment modalities are needed to reinvigorate immunosurveillance in immune-refractory tumors. An option to elicit antitumor immunity against cancer consists of using approved [...] Read more.
Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have considerably improved the treatment of some cancers, but novel drugs, new combinations, and treatment modalities are needed to reinvigorate immunosurveillance in immune-refractory tumors. An option to elicit antitumor immunity against cancer consists of using approved and marketed drugs known for their capacity to modulate the expression and functioning of the PD-1/PD-L1 checkpoint. Here, we have reviewed several types of drugs known to alter the checkpoint, either directly via the blockade of PD-L1 or indirectly via an action on upstream effectors (such as STAT3) to suppress PD-L1 transcription or to induce its proteasomal degradation. Specifically, the repositioning of the approved drugs liothyronine, azelnidipine (and related dihydropyridine calcium channel blockers), niclosamide, albendazole/flubendazole, and a few other modulators of the PD-1/PD-L1 checkpoint (repaglinide, pimozide, fenofibrate, lonazolac, propranolol) is presented. Their capacity to bind to PD-L1 or to repress its expression and function offer novel perspectives for combination with PD-1 targeted biotherapeutics. These known and affordable drugs could be useful to improve the therapy of cancer. Full article
(This article belongs to the Special Issue Checkpoint Markers and Cancer Microenvironment: What Do We Know?)
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