BioProject

Recent studies have demonstrated that b-catenin in dendritic cells (DCs) serves as a key mediator in promoting both CD4 and CD8 T cell tolerance, although the mechanisms underlying how b-catenin exerts its functions remains incompletely understood. More...

Recent studies have demonstrated that b-catenin in dendritic cells (DCs) serves as a key mediator in promoting both CD4 and CD8 T cell tolerance, although the mechanisms underlying how b-catenin exerts its functions remains incompletely understood. Here we report that activation of b-catenin leads to the up-regulation of inhibitory molecule T-cell immunoglobulin and mucin domain 3 (Tim-3) in type 1 conventional DCs (cDC1s). 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-b-cateninactive mice exhibited impaired cross-priming and memory re-sponses of gp100-specific CD8 T (Pmel-1) cells upon immunization with anti-DEC-205-hgp100. Sin-gle cell RNA sequencing (scRNA-seq) analysis revealed that b-catenin in DCs negatively regulated transcription programs for effector function and proliferation of primed Pmel-1 cells, correlating with suppressed CD8 T cell immunity in CD11c-b-cateninactive mice. Further experiments showed that treating CD11c-b-cateninactive mice with anti-Tim-3 antibody upon anti-DEC-205-hgp100 vac-cination led to restored cross-priming and memory responses of gp100-specific CD8 T cells, sug-gesting that anti-Tim-3 treatment likely synergizes with DC vaccines to improve their efficacy. In-deed, treating B16F10-bearing mice with DC vaccines using anti-DEC-205-hgp100 in combination with anti-Tim-3 treatment resulted in significantly reduced tumor growth, compared to treatment with DC vaccine alone. Taken together, we have identified the b-catenin/Tim-3 axis as a novel mech-anism 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. Overall design: We conducted scRNA-seq on transferred PMel-1 cells (from spleen) primed in WT or CD11c-b-catenin active mice. Less...