IL-17-induced HIF1 alpha drives resistance to anti-PD-L1 via fibroblast-mediated immune exclusion

This study uncovers a novel mechanism whereby IL-17 signaling drives immune exclusion by activating a HIF1 alpha-mediated collagen deposition program in cancer-associated fibroblasts in murine skin tumor models. Increasing evidence suggests that intratumoral inflammation has an outsized influence on antitumor immunity. Here, we report that IL-17, a proinflammatory cytokine widely associated with poor prognosis in solid tumors, drives the therapeutic failure of anti-PD-L1. By timing the deletion of IL-17 signaling specifically in cancer-associated fibroblasts (CAFs) in late-stage tumors, we show that IL-17 signaling drives immune exclusion by activating a collagen deposition program in murine models of cutaneous squamous cell carcinoma (cSCC). Ablation of IL-17 signaling in CAFs increased the infiltration of cytotoxic T cells into the tumor mass and sensitized otherwise resistant cSCC to anti-PD-L1 treatment. Mechanistically, the collagen deposition program in CAFs was driven by IL-17-induced translation of HIF1 alpha, which was mediated by direct binding of Act1, the adaptor protein of IL-17 receptor, to a stem-loop structure in the 3 ' untranslated region (UTR) in Hif1 alpha mRNA. Disruption of Act1's binding to Hif1 alpha mRNA abolished IL-17-induced collagen deposition and enhanced anti-PD-L1-mediated tumor regression.