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Cancers
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CD4 T Cells and Cancer Immune Response
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CD4 T Cells and Cancer Immune Response

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 20173

Special Issue Editors

Prof. Dr. Francois Ghiringhelli

E-Mail Website
Guest Editor
Department of Medical Oncology, Georges François Leclerc Cancer Center—UNICANCER, 21000 Dijon, France
Interests: digestive cancer; neuro-oncology; cancer immunotherapy; immune biomarkers; T cells antitumor immune response; immune effect of anticancer agents
Dr. Lionel Apetoh

E-Mail Website
Guest Editor
Inserm U1231, Dijon, France

Special Issue Information

Dear Colleagues,

CD4 T cells are key cell in the generation of adaptive immune response. CD4 T cells are initially produced in a “naive” form having not yet encountered any antigen. After recognition of a specific antigen presented by the antigen-major histocompatibility complex (MHC II) complex these cells become activated. Initially, CD4 immune response was described as a bimodal response which involved either Th1 or Th2 cells according to their cytokine secretions and functions. Th2, are characterized by a high production of IL-4, IL-5, and IL-13 and to a lesser and are necessary for protection against extracellular parasites. Th1 secrete interferon γ (IFNγ) and coordinate the immune response against intracellular microorganisms. Currently many additional subsets of CD4 T cells were described like regulatory T cells, follicular helper T cells, Th9 cells, Th17 cells. All these cells fine tune adaptive immune response. Importantly CD4 T cells immune response has a major role in the generation of antitumor immune response with some antitumoral or protumoral effect. In addition, CD4 immune response as also a major role for regulated CD8 exhausted program which is a major issue in the efficacy of checkpoint inhibitors.

The objective of this Special Issue is to gather original studies and reviews addressing the new knowledge available on CD4 T cells in the tumor environment. This Special Issue is expected to assemble studies analyzing the prognosis value of the different CD4 T cell subsets, the mechanisms involved in their recruitment and expansion in the tumor environment and their biological role in the tumor micro-environment and their capacity to affect CD8 exhaustion and response to checkpoint inhibitors.

Prof. Francois Ghiringhelli
Dr. Lionel Apetoh
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

  • CD4 T cells
  • molecular regulation
  • prognostic factor
  • immunotherapy
  • checkpoint inhibitors

Published Papers (5 papers)

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Research

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15 pages, 6815 KiB  
Article
Harnessing the IL-21-BATF Pathway in the CD8+ T Cell Anti-Tumor Response
by Paytsar Topchyan, Gang Xin, Yao Chen, Shikan Zheng, Robert Burns, Jian Shen, Moujtaba Y. Kasmani, Matthew Kudek, Na Yang and Weiguo Cui
Cancers 2021, 13(6), 1263; https://doi.org/10.3390/cancers13061263 - 12 Mar 2021
Cited by 18 | Viewed by 3317
Abstract
In cancer, CD8+ T cells enter a dysfunctional state which prevents them from effectively targeting and killing tumor cells. Tumor-infiltrating CD8+ T cells consist of a heterogeneous population of memory-like progenitor, effector, and terminally exhausted cells that exhibit differing functional and [...] Read more.
In cancer, CD8+ T cells enter a dysfunctional state which prevents them from effectively targeting and killing tumor cells. Tumor-infiltrating CD8+ T cells consist of a heterogeneous population of memory-like progenitor, effector, and terminally exhausted cells that exhibit differing functional and self-renewal capacities. Our recently published work has shown that interleukin (IL)-21-producing CD4+ T cells help to generate effector CD8+ T cells within the tumor, which results in enhanced tumor control. However, the molecular mechanisms by which CD4+ helper T cells regulate the differentiation of effector CD8+ T cells are not well understood. In this study, we found that Basic Leucine Zipper ATF-Like Transcription Factor (BATF), a transcription factor downstream of IL-21 signaling, is critical to maintain CD8+ T cell effector function within the tumor. Using mixed bone marrow chimeras, we demonstrated that CD8+ T cell-specific deletion of BATF resulted in impaired tumor control. In contrast, overexpressing BATF in CD8+ T cells enhanced effector function and resulted in improved tumor control, bypassing the need for CD4+ helper T cells. Transcriptomic analyses revealed that BATF-overexpressing CD8+ T cells had increased expression of costimulatory receptors, effector molecules, and transcriptional regulators, which may contribute to their enhanced activation and effector function. Taken together, our study unravels a previously unappreciated CD4+ T cell-derived IL-21–BATF axis that could provide therapeutic insights to enhance effector CD8+ T cell function to fight cancer. Full article
(This article belongs to the Special Issue CD4 T Cells and Cancer Immune Response)
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20 pages, 7963 KiB  
Article
Immunophenotype of Gastric Tumors Unveils a Pleiotropic Role of Regulatory T Cells in Tumor Development
by Sara Rocha, Afonso P Basto, Marieke E Ijsselsteijn, Sara P Teles, Maria M Azevedo, Gilza Gonçalves, Irene Gullo, Gabriela M Almeida, Joaquín J Maqueda, Marta I Oliveira, Fátima Carneiro, João T Barata, Luís Graça, Noel F C C de Miranda, Joana Carvalho and Carla Oliveira
Cancers 2021, 13(3), 421; https://doi.org/10.3390/cancers13030421 - 23 Jan 2021
Cited by 6 | Viewed by 3300
Abstract
Gastric cancer (GC) patients display increased regulatory T cell (Tregs) numbers in peripheral blood and among tumor-infiltrating lymphocytes. Nevertheless, the role of Tregs in GC progression remains controversial. Here, we sought to explore the impact of Tregs in GCs with distinct histology, and [...] Read more.
Gastric cancer (GC) patients display increased regulatory T cell (Tregs) numbers in peripheral blood and among tumor-infiltrating lymphocytes. Nevertheless, the role of Tregs in GC progression remains controversial. Here, we sought to explore the impact of Tregs in GCs with distinct histology, and whether Tregs can directly influence tumor cell behavior and GC development. We performed a comprehensive immunophenotyping of 82 human GC cases, through an integrated analysis of multispectral immunofluorescence detection of T cells markers and patient clinicopathological data. Moreover, we developed 3D in vitro co-cultures with Tregs and tumor cells that were followed by high-throughput and light-sheet imaging, and their biological features studied with conventional/imaging flow cytometry and Western blotting. We showed that Tregs located at the tumor nest were frequent in intestinal-type GCs but did not associate with increased levels of effector T cells. Our in vitro results suggested that Tregs preferentially infiltrated intestinal-type GC spheroids, induced the expression of IL2Rα and activation of MAPK signaling pathway in tumor cells, and promoted spheroid growth. Accumulation of Tregs in intestinal-type GCs was increased at early stages of the stomach wall invasion and in the absence of vascular and perineural invasion. In this study, we proposed a non-immunosuppressive mechanism through which Tregs might directly modulate GC cells and thereby promote tumor growth. Our findings hold insightful implications for therapeutic strategies targeting intestinal-type GCs and other tumors with similar immune context. Full article
(This article belongs to the Special Issue CD4 T Cells and Cancer Immune Response)
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Review

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26 pages, 1734 KiB  
Review
Harnessing Antitumor CD4+ T Cells for Cancer Immunotherapy
by Myriam Ben Khelil, Yann Godet, Syrine Abdeljaoued, Christophe Borg, Olivier Adotévi and Romain Loyon
Cancers 2022, 14(1), 260; https://doi.org/10.3390/cancers14010260 - 5 Jan 2022
Cited by 25 | Viewed by 6351
Abstract
Over the past decades, CD4+ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4+ T cells during antitumor immunity. CD4+ T cells can [...] Read more.
Over the past decades, CD4+ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4+ T cells during antitumor immunity. CD4+ T cells can either suppress or promote the antitumor cytotoxic CD8+ T cell responses, either in secondary lymphoid organs or in the tumor. In this review, we provide an overview of the multifaceted role of different CD4+ T cell subsets in cancer immune response and their contribution during cancer therapies. Specifically, we focus on the latest progress regarding the impact of CD4+ T cell modulation on immunotherapies and other cancer therapies and discuss the prospect for harnessing CD4+ T cells to control tumor progression and prevent recurrence in patients. Full article
(This article belongs to the Special Issue CD4 T Cells and Cancer Immune Response)
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20 pages, 915 KiB  
Review
Modulation of CD4 T Cell Response According to Tumor Cytokine Microenvironment
by Théo Accogli, Mélanie Bruchard and Frédérique Végran
Cancers 2021, 13(3), 373; https://doi.org/10.3390/cancers13030373 - 20 Jan 2021
Cited by 14 | Viewed by 3536
Abstract
The advancement of knowledge on tumor biology over the past decades has demonstrated a close link between tumor cells and cells of the immune system. In this context, cytokines have a major role because they act as intermediaries in the communication into the [...] Read more.
The advancement of knowledge on tumor biology over the past decades has demonstrated a close link between tumor cells and cells of the immune system. In this context, cytokines have a major role because they act as intermediaries in the communication into the tumor bed. Cytokines play an important role in the homeostasis of innate and adaptive immunity. In particular, they participate in the differentiation of CD4 T lymphocytes. These cells play essential functions in the anti-tumor immune response but can also be corrupted by tumors. The differentiation of naïve CD4 T cells depends on the cytokine environment in which they are activated. Additionally, at the tumor site, their activity can also be modulated according to the cytokines of the tumor microenvironment. Thus, polarized CD4 T lymphocytes can see their phenotype evolve, demonstrating functional plasticity. Knowledge of the impact of these cytokines on the functions of CD4 T cells is currently a source of innovation, for therapeutic purposes. In this review, we discuss the impact of the major cytokines present in tumors on CD4 T cells. In addition, we summarize the main therapeutic strategies that can modulate the CD4 response through their impact on cytokine production. Full article
(This article belongs to the Special Issue CD4 T Cells and Cancer Immune Response)
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13 pages, 1781 KiB  
Review
Unveiling the Hidden Treasury: CIITA-Driven MHC Class II Expression in Tumor Cells to Dig up the Relevant Repertoire of Tumor Antigens for Optimal Stimulation of Tumor Specific CD4+ T Helper Cells
by Greta Forlani, Mariam Shallak, Fabrizio Celesti and Roberto S. Accolla
Cancers 2020, 12(11), 3181; https://doi.org/10.3390/cancers12113181 - 29 Oct 2020
Cited by 9 | Viewed by 2907
Abstract
Despite the recent enthusiasm generated by novel immunotherapeutic approaches against cancer based on immune checkpoint inhibitors, it becomes increasingly clear that single immune-based strategies are not sufficient to defeat the various forms and types of tumors. Within this frame, novel vaccination strategies that [...] Read more.
Despite the recent enthusiasm generated by novel immunotherapeutic approaches against cancer based on immune checkpoint inhibitors, it becomes increasingly clear that single immune-based strategies are not sufficient to defeat the various forms and types of tumors. Within this frame, novel vaccination strategies that are based on optimal stimulation of the key cell governing adaptive immunity, the CD4+ T helper cell, will certainly help in constructing more efficient treatments. In this review, we will focus on this aspect, mainly describing our past and recent contributions that, starting with a rather unorthodox approach, have ended up with the proposition of a new idea for making available an unprecedented extended repertoire of tumor antigens, both in quantitative and qualitative terms, to tumor-specific CD4+ T helper cells. Our approach is based on rendering the very same tumor cells antigen presenting cells for their own tumor antigens by gene transfer of CIITA, the major transcriptional coordinator of MHC class II expression discovered in our laboratory. CIITA-driven MHC class II-expressing tumor cells optimally stimulate in vivo tumor specific MHC class II-restricted CD4 T cells generating specific and long lasting protective immunity against the tumor. We will discuss the mechanism underlying protection and elaborate not only on the applicability of this approach for novel vaccination strategies amenable to clinical setting, but also on the consequence of our discoveries on sedimented immunological dogmas that are related to antigen presentation. Full article
(This article belongs to the Special Issue CD4 T Cells and Cancer Immune Response)
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