β-catenin in dendritic cells negatively regulates CD8 T cell immune responses through the immune checkpoint molecule Tim-3 4802

Abstract Description Recent studies have demonstrated that β-catenin in DCs serves as a key mediator in promoting both CD4 and CD8 T cell tolerance, although how β-catenin exerts its functions remains incompletely understood. Here we report that activation of β-catenin leads to the up-regulation of inhibitory molecule T-cell immunoglobulin and mucin domain 3 (Tim-3) in cDC1s (type 1 conventional DCs). Using a cDC1-targeted vaccine model with anti-DEC-205 engineered to express the melanoma antigen--human gp100 (anti-DEC-205-hgp100), we demonstrated that CD11c-β-cateninactive mice exhibited impaired cross-priming upon immunization with anti-DEC-205-hgp100, resulting in much reduced memory responses. Further experiments revealed that treating CD11c-β-cateninactive mice with anti-Tim-3 antibody upon anti-DEC-205-hgp100 vaccination leads to restored cross-priming of gp100-specific CD8 T cells, suggesting that anti-Tim-3 treatment likely synergizes with DC vaccines to improve their efficacy. Indeed, treating B16F10-bearing mice with DC vaccines using anti-DEC-205-hgp100 in combination with anti-Tim-3 treatment resulted in significantly reduced tumors, compared to treatment with DC vaccine alone. Taken together, we have identified the β-catenin/Tim-3 axis as a novel mechanism to inhibit anti-tumor CD8 T cell immunity, and that combination immunotherapy of a DC-targeted vaccine with anti-Tim-3 treatment leads to improved anti-tumor efficacy. Funding Sources This work was supported by an internal grant from Henry Ford Health System (A30966) and R01CA198105 (to A.J.), 1R01CA284740, and 1R56AI165991 (to Q-S.M. and L.Z), and the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) grants SFB 1292/2 TP20 [Project Nr. 318346496], TRR 355/1 A09 [Project Nr. 490846870], and CL 419/2-2 [Project Nr. 315501751] (to B.E.C.). Topic Categories Vaccines and Immunotherapy (VAC)