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T Cells in Cancer Immunotherapy
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T Cells in Cancer Immunotherapy

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 (30 April 2023) | Viewed by 9477

Special Issue Editors

Dr. Luigi Nezi

E-Mail Website
Guest Editor
Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy
Interests: microbiome; immunology; immunotherapy; melanoma; colorectal cancer; tumor microenvironment; immune metabolism
Special Issues, Collections and Topics in MDPI journals
Dr. Teresa Manzo

E-Mail Website
Guest Editor
Immunometabolism and Cancer Immunotherapy Unit, IRCCS Istituto Europeo di Oncologia, 20139 Milan, Italy
Interests: dendritic cells; cross-priming; Flt3 ligand protein

Special Issue Information

Dear Colleagues,

The advent of immunotherapy has revolutionized cancer treatment by harnessing T cells to recognize and destroy cancer cells, with complete and durable clinical responses having been achieved in patients whose cancers were resistant to available standard treatments. Yet, this achievement has been met with limited success in most patients with solid tumors.

Therapeutic results have been heterogeneous, with better outcomes generally correlating with the ability of tumor-specific T cells to infiltrate the tumor, persist, and retain effector functions. T cells are key effectors of antitumor immunity; however, tumor-infiltrating T cells often acquire an altered state of dysfunction and, as a result, fail to control tumor outgrowth.

Scientists in our research field brought fundamental new insights concerning the mechanism governing anti-tumor T cell responses, paving the way for the development of new strategies to improve the immunotherapeutic treatment of cancer.

For this Special Issue of IJMS on “T cell and Cancer Immunotherapy”, we look forward to publishing the latest top-quality updates in the emerging area of tumor immunology, highlighting their importance to the field of immunotherapy research. We will accept both review and original articles with a focus on, but not limited to, the mechanisms tailoring T cell anti-tumor responses, understanding the impact of metabolic cross-talk between the tumor and immune cell, the mechanisms behind T cell exhaustion, the impact of gut microbiota on immunotherapy response, and new strategies to reprogram T cells and unleash their anti-tumor potential.

The goal of this Special Issue is to inform and guide the development of new and efficacious immunotherapeutic strategies, and to broaden their application for the treatment of refractory solid tumors.

Dr. Luigi Nezi
Dr. Teresa Manzo
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Published Papers (4 papers)

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Research

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18 pages, 6540 KiB  
Article
Comparative Evaluation of STEAP1 Targeting Chimeric Antigen Receptors with Different Costimulatory Domains and Spacers
by Yixin Jin, Claire Dunn, Irene Persiconi, Adam Sike, Gjertrud Skorstad, Carole Beck and Jon Amund Kyte
Int. J. Mol. Sci. 2024, 25(1), 586; https://doi.org/10.3390/ijms25010586 - 2 Jan 2024
Viewed by 1942
Abstract
We have developed a chimeric antigen receptor (CAR) against the six-transmembrane epithelial antigen of prostate-1 (STEAP1), which is expressed in prostate cancer, Ewing sarcoma, and other malignancies. In the present study, we investigated the effect of substituting costimulatory domains and spacers in this [...] Read more.
We have developed a chimeric antigen receptor (CAR) against the six-transmembrane epithelial antigen of prostate-1 (STEAP1), which is expressed in prostate cancer, Ewing sarcoma, and other malignancies. In the present study, we investigated the effect of substituting costimulatory domains and spacers in this STEAP1 CAR. We cloned four CAR constructs with either CD28 or 4-1BB costimulatory domains, combined with a CD8a-spacer (sp) or a mutated IgG-spacer. The CAR T-cells were evaluated in short- and long-term in vitro T-cell assays, measuring cytokine production, tumor cell killing, and CAR T-cell expansion and phenotype. A xenograft mouse model of prostate cancer was used for in vivo comparison. All four CAR constructs conferred CD4+ and CD8+ T cells with STEAP1-specific functionality. A CD8sp_41BBz construct and an IgGsp_CD28z construct were selected for a more extensive comparison. The IgGsp_CD28z CAR gave stronger cytokine responses and killing in overnight caspase assays. However, the 41BB-containing CAR mediated more killing (IncuCyte) over one week. Upon six repeated stimulations, the CD8sp_41BBz CAR T cells showed superior expansion and lower expression of exhaustion markers (PD1, LAG3, TIGIT, TIM3, and CD25). In vivo, both the CAR T variants had comparable anti-tumor activity, but persisting CAR T-cells in tumors were only detected for the 41BBz variant. In conclusion, the CD8sp_41BBz STEAP1 CAR T cells had superior expansion and survival in vitro and in vivo, compared to the IgGsp_CD28z counterpart, and a less exhausted phenotype upon repeated antigen exposure. Such persistence may be important for clinical efficacy. Full article
(This article belongs to the Special Issue T Cells in Cancer Immunotherapy)
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Review

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15 pages, 960 KiB  
Review
Targeting Immunosuppressive Adenosine Signaling: A Review of Potential Immunotherapy Combination Strategies
by David Zahavi and James W. Hodge
Int. J. Mol. Sci. 2023, 24(10), 8871; https://doi.org/10.3390/ijms24108871 - 17 May 2023
Cited by 5 | Viewed by 2101
Abstract
The tumor microenvironment regulates many aspects of cancer progression and anti-tumor immunity. Cancer cells employ a variety of immunosuppressive mechanisms to dampen immune cell function in the tumor microenvironment. While immunotherapies that target these mechanisms, such as immune checkpoint blockade, have had notable [...] Read more.
The tumor microenvironment regulates many aspects of cancer progression and anti-tumor immunity. Cancer cells employ a variety of immunosuppressive mechanisms to dampen immune cell function in the tumor microenvironment. While immunotherapies that target these mechanisms, such as immune checkpoint blockade, have had notable clinical success, resistance is common, and there is an urgent need to identify additional targets. Extracellular adenosine, a metabolite of ATP, is found at high levels in the tumor microenvironment and has potent immunosuppressive properties. Targeting members of the adenosine signaling pathway represents a promising immunotherapeutic modality that can potentially synergize with conventional anti-cancer treatment strategies. In this review, we discuss the role of adenosine in cancer, present preclinical and clinical data on the efficacy adenosine pathway inhibition, and discuss possible combinatorial approaches. Full article
(This article belongs to the Special Issue T Cells in Cancer Immunotherapy)
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14 pages, 1317 KiB  
Review
BTN3A: A Promising Immune Checkpoint for Cancer Prognosis and Treatment
by Abdou-samad Kone, Saadia Ait Ssi, Souha Sahraoui and Abdallah Badou
Int. J. Mol. Sci. 2022, 23(21), 13424; https://doi.org/10.3390/ijms232113424 - 3 Nov 2022
Cited by 6 | Viewed by 2557
Abstract
Butyrophilin-3A (BTN3A) subfamily members are a group of immunoglobulins present on the surface of different cell types, including innate and cancer cells. Due to their high similarity with the B7 family members, different studies have been conducted and revealed the involvement of BTN3A [...] Read more.
Butyrophilin-3A (BTN3A) subfamily members are a group of immunoglobulins present on the surface of different cell types, including innate and cancer cells. Due to their high similarity with the B7 family members, different studies have been conducted and revealed the involvement of BTN3A molecules in modulating T cell activity within the tumor microenvironment (TME). However, a great part of this research focused on γδ T cells and how BTN3A contributes to their functions. In this review, we will depict the roles and various aspects of BTN3A molecules in distinct tumor microenvironments and review how BTN3A receptors modulate diverse immune effector functions including those of CD4+ (Th1), cytotoxic CD8+ T cells, and NK cells. We will also highlight the potential of BTN3A molecules as therapeutic targets for effective immunotherapy and successful cancer control, which could represent a bright future for patient treatment. Full article
(This article belongs to the Special Issue T Cells in Cancer Immunotherapy)
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19 pages, 1244 KiB  
Review
Systemic CD4 Immunity and PD-L1/PD-1 Blockade Immunotherapy
by David Escors, Ana Bocanegra, Luisa Chocarro, Ester Blanco, Sergio Piñeiro-Hermida, Maider Garnica, Leticia Fernandez-Rubio, Ruth Vera, Hugo Arasanz and Grazyna Kochan
Int. J. Mol. Sci. 2022, 23(21), 13241; https://doi.org/10.3390/ijms232113241 - 31 Oct 2022
Cited by 6 | Viewed by 2325
Abstract
PD-L1/PD-1 blockade immunotherapy has changed the therapeutic approaches for the treatment of many cancers. Nevertheless, the mechanisms underlying its efficacy or treatment failure are still unclear. Proficient systemic immunity seems to be a prerequisite for efficacy, as recently shown in patients and in [...] Read more.
PD-L1/PD-1 blockade immunotherapy has changed the therapeutic approaches for the treatment of many cancers. Nevertheless, the mechanisms underlying its efficacy or treatment failure are still unclear. Proficient systemic immunity seems to be a prerequisite for efficacy, as recently shown in patients and in mouse models. It is widely accepted that expansion of anti-tumor CD8 T cell populations is principally responsible for anti-tumor responses. In contrast, the role of CD4 T cells has been less studied. Here we review and discuss the evidence supporting the contribution of CD4 T cells to anti-tumor immunity, especially recent advances linking CD4 T cell subsets to efficacious PD-L1/PD-1 blockade immunotherapy. We also discuss the role of CD4 T cell memory subsets present in peripheral blood before the start of immunotherapies, and their utility as predictors of response. Full article
(This article belongs to the Special Issue T Cells in Cancer Immunotherapy)
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