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Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.
- Source :
-
Nature [Nature] 2024 Aug; Vol. 632 (8023), pp. 182-191. Date of Electronic Publication: 2024 Jul 24. - Publication Year :
- 2024
-
Abstract
- CD4 <superscript>+</superscript> T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses <superscript>1-5</superscript> , other CD4 <superscript>+</superscript> T cells have recently been implicated in inhibiting this response <superscript>6,7</superscript> . Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Female
Humans
Male
Mice
Cancer Vaccines immunology
Cancer Vaccines therapeutic use
Cell Line, Tumor
Chemokine CCL5 metabolism
Dendritic Cells immunology
Granzymes metabolism
Histocompatibility Antigens Class I immunology
Histocompatibility Antigens Class II immunology
Interleukin-10 metabolism
Interleukin-10 immunology
Mice, Inbred C57BL
Receptors, Immunologic antagonists & inhibitors
Membrane Glycoproteins antagonists & inhibitors
Immune Tolerance
CD8-Positive T-Lymphocytes immunology
Antigens, Neoplasm immunology
CD4-Positive T-Lymphocytes immunology
CD4-Positive T-Lymphocytes metabolism
Immunotherapy
Neoplasms immunology
Neoplasms therapy
T-Lymphocytes, Regulatory immunology
Cytotoxicity, Immunologic
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 632
- Issue :
- 8023
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 39048822
- Full Text :
- https://doi.org/10.1038/s41586-024-07752-y