1. Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.
- Author
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Sultan, Hussein, Takeuchi, Yoshiko, Ward, Jeffrey P., Sharma, Naveen, Liu, Tian-Tian, Sukhov, Vladimir, Firulyova, Maria, Song, Yuang, Ameh, Samuel, Brioschi, Simone, Khantakova, Darya, Arthur, Cora D., White, J. Michael, Kohlmiller, Heather, Salazar, Andres M., Burns, Robert, Costa, Helio A., Moynihan, Kelly D., Yeung, Yik Andy, and Djuretic, Ivana
- 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.Type 1 regulatory T cells (Tr1) represent a major obstacle that compromises naturally occurring and therapeutically induced tumour-specific immunity. [ABSTRACT FROM AUTHOR]- Published
- 2024
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