A paradoxical role for classical dendritic cells and Flt3 ligand in tumor immune response

Abstract

Abstract Flt3 ligand (FL) induces differentiation and proliferation of classical dendritic cells (cDCs) and is a promising molecule in therapies of cancer and vaccination, but has mixed effects in clinical trials. The role of cDCs in antitumor response is ambiguous as they may induce priming of anti-tumor lymphocytes, but also may favor recruitment of tumor-protecting regulatory T cells (Tregs). To better understand the role of FL/DCs axis in cancer, we monitored tumor growth in a mouse model of melanoma in the context of low, normal or high levels of FL. Paradoxically, both genetic FL depletion and overexpression stalled tumor growth and increased animal survival as compared to control. We show that FL-deficient mice tumor growth is predominantly controlled by the adaptive immune system unleashed by a diminution of Tregs, while high FL levels favor the innate anti-tumor response through the recruitment of NK cells. Analysis of human gene expression data confirmed the paradoxical effect of FL as well as cDCs on survival in several types of cancer. Tumor samples from patients in these groups expressed Treg and NK cells signatures in correlation with the levels of cDCs, FL, IL15 and IL15RA expression. As a proof-of-principle, we showed that the combination of FL overexpression and Tregs depletion resulted in regression of established tumors in mice. We propose that FL is a master regulator of immune control of tumor growth owing to its key role in DCs function.