CD91-mediated reprogramming of DCs by immunogenic heat shock proteins requires the kinases AXL and Fgr

Immune responses to tumors, comprising adaptive T cells and innate NK cells, arise very early in tumorigeneses and prior to detection of palpable tumors or before tissue pathology is evident. Yet, how nascent tumors evoke dendritic cell maturation and the resulting cytokine responses that are necessary for these effector anti-tumor immune responses is unknown. We have previously shown that CD91 expression on dendritic cells is important for immune surveillance, specifically for generating T cell and NK cell responses to nascent tumors. Here we show that engagement of CD91 by its ligands, the tumor-derived HSPs, triggers intracellular signaling within the dendritic cell and reprograms them to release cytokines and become receptive to other immune mediators. We identify AXL and Fgr as essential adaptor kinases that physically associate with, and phosphorylate, CD91 and are important for transmission of distinct but overlapping signaling in cells. Inhibition of these kinases prevents HSP-induced phosphorylation of signaling cascade components and downstream cytokine production. We show that two different immunogenic HSPs that bind CD91 differentially utilize AXL and Fgr and activate distinct programming of dendritic cells, which is important for the varied immunological responses that tumors evoke. Overall, these findings describe an innate sensing mechanism of nascent tumors by dendritic cells, resulting in initiation of anti-tumor responses via the HSP-CD91 axis.