%0 Journal Article
%T Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.
%A Sultan H
%A Takeuchi Y
%A Ward JP
%A Sharma N
%A Liu TT
%A Sukhov V
%A Firulyova M
%A Song Y
%A Ameh S
%A Brioschi S
%A Khantakova D
%A Arthur CD
%A White JM
%A Kohlmiller H
%A Salazar AM
%A Burns R
%A Costa HA
%A Moynihan KD
%A Yeung YA
%A Djuretic I
%A Schumacher TN
%A Sheehan KCF
%A Colonna M
%A Allison JP
%A Murphy KM
%A Artyomov MN
%A Schreiber RD
%J Nature
%V 632
%N 8023
%D 2024 Aug 24
%M 39048822
%F 69.504
%R 10.1038/s41586-024-07752-y
%X 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.