Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy

• 成果类型: Article
• 署名作者: 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; Djuretic, Ivana; Schumacher, Ton N.; Sheehan, Kathleen C. F.; Colonna, Marco; Allison, James P.; Murphy, Kenneth M.; Artyomov, Maxim N.; Schreiber, Robert D.
• 署名单位: Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); University of Texas System; UTMD Anderson Cancer Center; Almazov National Medical Research Centre; Natera, Inc.; Netherlands Cancer Institute; Leiden University; Leiden University - Excl LUMC
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4588
• DOI: 10.1038/s41586-024-07752-y
• 发表日期: 2024-08-08
• 关键词: dendritic cells; inhibitory receptor; expression; vaccine; ilt3; lymphocytes; induction; responses

摘要

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.