1. Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.
- Author
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Sultan H, Takeuchi Y, Ward JP, Sharma N, Liu TT, Sukhov V, Firulyova M, Song Y, Ameh S, Brioschi S, Khantakova D, Arthur CD, White JM, Kohlmiller H, Salazar AM, Burns R, Costa HA, Moynihan KD, Yeung YA, Djuretic I, Schumacher TN, Sheehan KCF, Colonna M, Allison JP, Murphy KM, Artyomov MN, and Schreiber RD
- 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
- Abstract
CD4
+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1-5 , other CD4+ T cells have recently been implicated in inhibiting this response6,7 . 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., (© 2024. The Author(s).)- Published
- 2024
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