Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox

Oh, David Y.; Fong, Lawrence

doi:10.1016/j.immuni.2021.11.015

Cited by 476T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox

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Oh, David Y., Fong, Lawrence·2021·Immunity

DOI 10.1016/j.immuni.2021.11.015PMC PMC8809482

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Abstract

Cytotoxic T cells are important effectors of anti-tumor immunity. While tumor killing is ascribed to CD8 + T cell function, pre-clinical and clinical studies have identified intra-tumoral CD4 + T cells that possess cytotoxic programs and can directly kill cancer cells. Cytotoxic CD4 + T cells are found in other disease settings including infection and autoimmunity. Here, we review the phenotypic and functional characteristics of cytotoxic CD4 + T cells in non-cancer and cancer contexts. We conduct a comparative examination of cytolytic mechanisms of cytotoxic CD4 + T cells across disease states and synthesize features that define these cells independent of context. We discuss regulatory mechanisms driving ontogeny and effector function and evidence for the clinical relevance of cytotoxic CD4 + T cells in cancer. In this context, we highlight important gaps in understanding in the biology of cytotoxic CD4 + T cells as well as the potential use of these cells in immunotherapies for specific cancers.

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In post-cryoablated RMS 76-9STINGwt TME compared with RMS 76-9STING-/- TME in wild-type mice, there was a significant increase in total CD4+ T cells expressing IFN-γ and GZMB, NK cells, GZMB expression in CD8+ T cells, and Foxp3+ CD4+ cells.
“we observed a significant increase in the total CD4+ T cells expressing IFN-γ (figure 4H) and granzyme B (GZMB; figure 4J),60–65 NK cells (figure 4N), and the amount of GZMB expression in CD8+ T cells (figure 4L) in the post-cryoablated RMS 76-9STINGwt TME as compared with RMS 76-9STING-/- TME in wild-type mice, as was Foxp3+ CD4+ cells (figure 4M).”
From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [64]
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Authors: Oh, D. Y., & Fong, L.
Affiliations: University of California, San Francisco (US)
Corresponding author: Fong, Lawrence
ORCID: Oh, David Y.
Fong, Lawrence
Venue: Immunity
Publisher: Elsevier BV
Published: 2021-12
Volume: 54
Issue: 12
Pages: 2701-2711
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2021.11.015
PMC: PMC8809482
OpenAlex: W4200244347
Cited by: 467
References: 73
Citations by year: 2026: 81 · 2025: 127 · 2024: 116 · 2023: 101 · 2022: 41 · 2021: 1
FWCI: 6.86
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Immunity (publishedVersion, cc-by)
PubMed (publishedVersion)
PubMed Central (acceptedVersion, cc-by)
eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders: NCI
National Institutes of Health (K08AI139375)
Prostate Cancer Foundation (R35CA253175)
Bavarian Nordic
Genentech
Parker Institute for Cancer Immunotherapy
AbbVie
Amgen
Merck
Merck KGaA
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: cytotoxic CD4+ T cells, antitumor immunity, cytotoxicity mechanism, cancer immunotherapy, infection, autoimmunity
MeSH terms: Animals, Cytotoxicity, Immunologic, Humans, Neoplasms, T-Lymphocytes, Cytotoxic, CD4-Positive T-Lymphocytes, Immunotherapy, Adoptive

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Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox

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