XCR1+ and IRF4+ migratory dendritic cells cooperate for the cross-priming of intratumoral CD8+ T cells with a tissue-resident memory phenotype.

The composition and diversity of tumor-infiltrating CD8⁺ T cell populations have important consequences on the development of anti-tumor immunity. In a murine model of lung cancer, we have addressed the role of dendritic cell subsets on the generation of various types of tumor-infiltrating CD8⁺ T cells. We show that CD44⁺PD1^- effector and PD1⁺TIM3⁺ exhausted, tumor-infiltrating CD8⁺ T cells require XCR1⁺ DCs but not IRF4-dependent DCs. By contrast, CD103⁺CXCR6⁺ T_RM-like, tumor-infiltrating CD8⁺ T cells require both XCR1⁺ DCs and IRF4-dependent DCs. The same requirement is found in tumor-draining lymph nodes where we identify CD103⁺CXCR6⁺ T_RM-like precursors that are dependent on both XCR1⁺ DCs and IRF4-dependent migratory DCs. Mechanistically, we evidence that both types of migratory DCs cooperate. Mild TCR triggering by low MHCI-peptide density at the surface of cross-presenting migratory DC2s and low IL-12 support TGFb-dependent T_RM specification in lymph nodes. High TCR triggering and high MHCI-peptide density at the surface of cross-presenting migratory DC1s and high IL-12 support proliferative expansion and CXCR6 acquisition. Altogether, these findings highlight the induction of intratumoral T_RM-like cells under the collective aegis of multiple DCs subsets within tumor-draining lymph nodes reconciliating T_RM phenotype instruction with proliferative expansion.