Dendritic Cell Maturation Defines Immunological Responsiveness of Tumors and Radiation

Radiation therapy is capable of directing adaptive immune responses against tumors by stimulating the release of endogenous adjuvants and tumor-associated antigens. Within the tumor, conventional type 1 dendritic cells (cDC1s) are uniquely positioned to respond to these signals, uptake exogenous tumor antigens and migrate to the tumor draining lymph node (dLN) to initiate cross-priming of tumor reactive cytotoxic CD8+ T cells. Here we report that radiation therapy promotes the activation of intratumoral cDC1s in immunogenic tumors and this process fails to occur in poorly immunogenic tumors. In poorly immunogenic tumors, the adjuvant poly I:C overcomes this failure following radiation and successfully drives intratumoral cDC1 maturation, ultimately resulting in durable tumor cures. Depletion studies revealed that both cDC1s and CD8+ T cells are required for tumor regression following combination therapy. We further demonstrate that treatment with radiation and poly I:C significantly expands the proportion of proliferating CD8+ T cells in the tumor with enhanced cytolytic potential and requires T cell migration from LNs for therapeutic efficacy. Thus, we conclude that lack of endogenous adjuvant release or active suppression following radiation therapy may limit its efficacy in poorly immunogenic tumors, and co-administration of exogenous adjuvants that promote cDC1 maturation and migration can overcome this limitation to improve tumor control following radiation therapy