Flt3L-mediated tumor cDC1 expansion enhances immunotherapy by priming stem-like CD8⁺ T cells in lymph nodes

Immune checkpoint blockade (ICB) evokes antitumor immunity through the reinvigoration of T cell responses. T cell differentiation status controls response, with less differentiated cells having an enhanced capacity to proliferate after ICB. Given that conventional type 1 dendritic cells (cDC1) maintain precursor exhausted T cells (T_PEX), we hypothesized that expansion of cDC1s with Flt3L could enhance responses to ICB. Here we show that treatment with Fms-related tyrosine kinase 3 ligand (Flt3L) expands CD62L⁺SLAMF6⁺CD8⁺ T cells in the tumor through a mechanism that requires XCR1⁺ dendritic cells to traffic to the tumor-draining lymph node. The combination of Flt3L and anti-CTLA-4 enhanced therapeutic responses. Combination therapy is associated with the emergence of a CD8⁺ T cell subset characterized by the expression of Il21r and oligoclonal expansion of CD8⁺ T cells within tumors through a mechanism that is dependent on lymph node egress.