Neoantigen-Specific Cytotoxic TR1 CD4 T Cells Suppress Cancer Immunotherapy

Authors

Hussein Sultan
Yoshiko Takeuchi
Jeffrey P Ward
Naveen Sharma
Tian-Tian Liu
Vladimir Sukhov
Maria Firulyova
Yuang Song
Samuel Ameh
Simone Brioschi
Darya Khantakova
Cora D Arthur
J Michael White
Heather Kohlmiller
Andres M Salazar
Robert Burns
Helio A Costa
Kelly D Moynihan
Yik Andy Yeung
Ivana Djuretic
Ton N Schumacher
Kathleen C F Sheehan
Marco Colonna
James P Allison
Kenneth M Murphy
Maxim N Artyomov
Robert D Schreiber

Publication Date

8-1-2024

Journal

Nature

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.

Keywords

Animals, Female, Humans, Male, Mice, Antigens, Neoplasm, Cancer Vaccines, CD4-Positive T-Lymphocytes, Cell Line, Tumor, Chemokine CCL5, Dendritic Cells, Granzymes, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Immunotherapy, Interleukin-10, Mice, Inbred C57BL, Neoplasms, T-Lymphocytes, Regulatory, Receptors, Immunologic, Membrane Glycoproteins, Cytotoxicity, Immunologic, Immune Tolerance, CD8-Positive T-Lymphocytes

Comments

Supplementary Materials

PMID: 39048822