FLT3L-dependent dendritic cells control tumor immunity by modulating Treg and NK cell homeostasis 2384

Abstract Description FLT3-L-dependent classical dendritic cells (cDCs) recruit anti-tumor and tumor-protecting lymphocytes. We evaluated cancer growth in mice with low, normal or high levels of cDCs. Paradoxically, both low or high numbers of cDCs improve survival in mice with melanoma. In low cDC context, tumors are restrained by the adaptive immune system through influx of activated effector T cells and decrease of Tregs and NK cells. High cDC numbers favor the innate anti-tumor response, with massive recruitment of activated NK cells, despite high Treg infiltration. Anti CTLA-4 but not anti PD-1 therapy synergizes with FLT3-L therapy in the cDCHi but has no effect in the cDCLo context, hinting that, in this model, Tregs and not Teffs are the main target of CTLA-4 ICBT. Combination of cDC boost and Treg depletion dramatically improves survival of tumor-bearing mice. We then examined Flt3-L, cDC1, cDC2 & pDCs gene signatures in the biopsies of untreated cancer patients with 42 types of cancer and identified a beneficial, adverse or paradoxical effect of these signatures in 35 types of human cancers. Thus, transcriptomic data confirm the paradoxical effect of cDC levels on survival in several human tumor types. cDCHi-TregLo state in such patients predicts best survival. These results have important implications for improving immunotherapy in specific types of cancer. Funding Sources La Ligue Contre le Cancer (TANC16319); China Scholarship Council (CSC202206240034) La Fondation ARC (PJA20141201668), Institut National Du Cancer (PLBIO2019-075). INSERM, Faculty of Medicine of Paris City University. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)