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.