Flt3L -expanded conventional type I dendritic cells formed in the tumor prime “stem-like” T cells in the draining lymph nodes to evoke enhanced responses to immunotherapy [1]

Immune checkpoint blockade (ICB) evokes anti-tumor immunity through the reinvigoration of tumor-specific T cell responses but it is only effective in a subset of patients. T cell differentiation status is a critical determinant of response, with less differentiated cells demonstrating an enhanced capacity to proliferate following ICB. Given recent data indicating that conventional type 1 dendritic cells (cDC1) maintain precursor exhausted (TPEX) cells, we hypothesized that expansion of cDC1s could enhance responses to ICB. Treatment of mice with Flt3L simultaneously expanded cDC1s and CD62L+SLAMF6+CD8+ T cells in both tumors and draining lymph nodes. The formation of these CD62L+SLAMF6+ CD8+ T cells is dependent on the transcription factor Myb, CCR7+ XCR1+DCs and lymph node egress. Hence, we demonstrate that the lymph node is a critical site for the effect of Flt3L on T cell differentiation state. We hypothesized that the promotion of this phenotype would enable more effective responses to ICB. Indeed, the combination of Flt3L and anti-CTLA4 led to significantly enhanced therapeutic responses and was associated with the emergence of a unique CD8+ T cell subset characterized by the expression of IL-21R. Single cell RNA profiling of whole 24JK or 24JK-FLT3L tumors. Harvested day 16, n=5 per group