The alarmin cytokine IL-1a drives a feedback-amplification loop between dying tumor cells and inflammatory monocyte-lineage dendritic cells

Abstract

Abstract Successful immunotherapy must transform the normally suppressive tumor microenvironment into a pro-inflammatory, immunogenic milieu. We show that this critical transformation depends on a previously unrecognized initiating signal delivered by the damage-associated “alarmin” cytokine interleukin-1a (IL-1a). Initially, tumor-intrinsic IL-1a was mobilized from dying tumor cells. This drove rapid local differentiation of a population of monocyte-lineage inflammatory dendritic cells (DCs). We have previously described these inflammation-inducible myeloid DCs in tumors (Sharma et. al, Immunity 48:91–106, 2018), where they serve as key antigen-presenting cells during multiple forms of immunotherapy and chemo-immuno-therapy. Once these inflammatory DCs were elicited by tumor-derived IL-1a, they rapidly re-activated anergic/unresponsive tumor-associated CD8+ T cells. Then DCs and T cells together produced reciprocal host-derived IL-1a, thus completing a potent self-amplifying feedback loop. If this IL-1a-driven feedback-amplification loop was disrupted – either by silencing IL-1a in the tumor cells; or ablating IL-1a in the host cells; or disrupting the IL-1-receptor on the inflammatory dendritic cells – then anti-tumor immune activation was lost across multiple forms of immunotherapy and chemotherapy. To restore the ability to initiate immune activation, the only cells that needed to respond to IL-1a were the specific population of inflammatory monocyte-lineage DCs.