Distinct migratory dendritic cell subsets cooperate to prime tissue-resident memory-like CD8⁺ T cells in mouse tumors

Abstract

Tumor-infiltrating tissue-resident memory (TRM)-like CD8+ T cells correlate with positive prognosis and better responses to cancer immunotherapy, yet the mechanisms underlying their specification remain ill-understood. Here, we use the KP (KrasG12D, p53-/-) mouse model of lung adenocarcinoma to investigate how different dendritic cell (DC) subsets shape tumor-specific CD8+ T cell responses. Selective ablation of XCR1+ DC1s or IRF4-dependent CD11b+ DC2s reveal that DC1s, but not DC2s, are required for the generation of tumor-infiltrating effector and exhausted CD8+ T cells. By contrast, both migratory DC1s and migratory DC2s contribute to the specification of CD103+CD69+ TRM-like CD8+ T cells in tumor-draining lymph nodes. Mechanistically, low peptide/MHC-I density on migratory DC2s favors TGFβ-dependent TRM differentiation, while high peptide/MHC-I density on DC1s promote proliferative expansion of TRM-like cells; in addition, IL-12 secreted by DC1s enhances CXCR6 expression. Together, our findings uncover complementary functions of migratory DC subsets in shaping anti-tumor TRM-like CD8+ T cell responses, and also implicate targeting multiple DC subsets for optimizing cancer immunotherapy. Tissue-resident memory (TRM) CD8+ T cells in the tumor microenvironment are relevant for anti-tumor immunity and immune checkpoint blockade response. Here, the authors conditionally ablate type 1 and type 2 dendritic cells in a lung cancer mouse model, finding both to be critical for the differentiation and expansion of TRM-like T cells.