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Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox
Open accessAbstract
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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“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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“T cells are the major component of infiltrated immune cells in most solid tumors, and CD8 + cytotoxic T cells (CTLs) and CD4 + T helper cells (Ths) play crucial roles in eliminating tumor cells[36,37].”
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Cytotoxic CD4 T cells in the mucosa and in cancer
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“The main immunosuppressive mechanism of cancer cells is intimately related to CD4+ and CD8+ T cells[15,16].”
Oncolytic virotherapy against lung cancer: key receptors and signaling pathways of viral entry
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“These cells are known as well as Th1 cells (167).”
BackgroundAlshebremi, M., Tomchuck, S. L., Myers, J. T., Kingsley, D. T., Eid, S., Abiff, M., Bonner, M., Saab, S. T., Choi, S. H., & Huang, A. Y.-C. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006608 · Cited by 14
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Specificity and function of T cell subset identities using single‐cell sequencing
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Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity
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Immune cell infiltration and inflammatory landscape in primary brain tumours
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The UBA1–STUB1 Axis Mediates Cancer Immune Escape and Resistance to Checkpoint Blockade
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“There is abundant evidence to demonstrate that cytosolic double-stranded DNA (dsDNA) originating from damaged cancer cells can directly promote the activation of the cGAS-STING pathway, thereby provoking the antitumor immunity [23].”
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Regulation of CD4 T Cell Responses by the Transcription Factor Eomesodermin
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Hao, Y., Miraghazadeh, B., Chand, R., Davies, A. R., Cardinez, C., Kwong, K., Downes, M. B., Sweet, R. A., Cañete, P. F., D'Orsogna, L. J. A., et al. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-01027-8 · Cited by 12
“Cytotoxic CD4 T cells have been implicated in host defense against virus infection and tumor cells [17, 18] and in the pathology of various diseases, including fibrotic autoimmune and inflammatory diseases [19, 20].”
BackgroundInfluentialDurable antitumor response via an oncolytic virus encoding decoy-resistant IL-18
Cheng, Y., Zhao, Y., Liu, Y., Zhang, Y., Xu, D., Sun, W., Zhang, M., Miao, Y., He, S., Hou, Y., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009716 · Cited by 13
“Finally, we performed ELISpot assays for IFN-γ release to determine the relative strength of the antitumor response among splenocytes activated by oAdDR18 of the CT26 tumor model.”
Chen, C., LIM, D. J., Cai, Z., Zhang, F., Liu, G., Dong, C., & Feng, Z. (2023) · Food and Chemical Toxicology · doi:10.1016/j.fct.2023.113783 · Cited by 11
Khabipov, A., Trung, D. N., van der Linde, J., Miebach, L., Lenz, M., Erne, F., von Bernstorff, W., Schulze, T., Kersting, S., Bekeschus, S., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11061517 · Cited by 11
“Considering the anti-tumorous attributes of CD4+ and CD8+ T cells, this result needs to be critically evaluated [63,64].”
BackgroundAntagonism of regulatory ISGs enhances the anti-melanoma efficacy of STING agonists
Filderman, J. N., Taylor, J. L., Wang, J., Zhang, Y., Singh, P. K., Ross, M. A., Watkins, S. C., Al-Bzour, A. N., Karapetyan, L., Kaliński, P., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1334769 · Cited by 11
“While we did not observe the same skewing of macrophages toward M1 TAMs or more mature DCs in our BPR model, we did note an increase in cytotoxic Granzyme B + CD4 + T cells known to mediate direct killing of MHC II+ tumor cells (54), as well as an increase in central memory CD4 + and CD8 + TIL.”
ResultLymph-Node Inspired Hydrogels Enhance CAR Expression and Proliferation of CAR T Cells
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Inflammatory dendritic cells restrain CD11b+CD4+ CTLs via CD200R in human NSCLC
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CD4+ CAR T cells — more than helpers
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“This observation unlocks a new gate for understanding its implication of targeting coinhibitory receptor LAG-3 that mechanistically crosstalk with MHC class II (142 – 145).”
BackgroundThe Potential Impact of HNRNPA2B1 on Human Cancers Prognosis and Immune Microenvironment
Huang, T., Zhu, G., & Chen, F. (2024) · Journal of Immunology Research · doi:10.1155/2024/5515307 · Cited by 9
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“Previous studies demonstrated CD8 and CD4’s correlation with CD8 + T cells and CD4 + T cells respectively, both capable of anti-tumor activity and predicting favorable immunotherapeutic outcomes [63, 64].”
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Glutamine metabolism and ammonia death: targeted modulation for enhanced cancer immunotherapy
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“Following activation and execution of their effector functions, the majority of effector CD4+ T cells undergo programmed cell death (apoptosis), making them unsuitable for long-term immunity (136, 137).”
Classic psychedelics do not affect T cell and monocyte immune responses
Rudin, D., Areesanan, A., Liechti, M. E., & Gründemann, C. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1042440 · Cited by 11
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“While the latter downregulate BCL6 and TCF7 and upre-gulate PRDM1 during differentiation from T FH cells, 31,32 the former maintain high expression of BCL6 and TCF7 and low expression of PRDM1 , suggesting a divergent differentiation trajectory shaped by the FL TME.”
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Cytotoxic T Cells: Kill, Memorize, and Mask to Maintain Immune Homeostasis
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“However, in recent years it has become increasingly clear that the effector functions of CD4+ T cells extend well beyond their “ helper ” role (35 – 37).”
Background
Metadata
- Authors
- Oh, D. Y., & Fong, L.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Fong, Lawrence
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 54
- Issue
- 12
- Pages
- 2701-2711
- ISSN
- 1074-7613 (ISSN-L)
- 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
- 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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