IL-17-induced HIF1α drives resistance to anti-PD-L1 via fibroblast-mediated immune exclusion

J Exp Med. 2022 Jun 6;219(6):e20210693. doi: 10.1084/jem.20210693. Epub 2022 Apr 7.


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 HIF1α, 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 Hif1α mRNA. Disruption of Act1's binding to Hif1α mRNA abolished IL-17-induced collagen deposition and enhanced anti-PD-L1-mediated tumor regression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B7-H1 Antigen / metabolism
  • Cancer-Associated Fibroblasts* / metabolism
  • Carcinoma, Squamous Cell* / immunology
  • Carcinoma, Squamous Cell* / pathology
  • Cell Line, Tumor
  • Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
  • Interleukin-17* / metabolism
  • Mice
  • RNA, Messenger
  • Skin Neoplasms* / immunology
  • Skin Neoplasms* / pathology


  • B7-H1 Antigen
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-17
  • RNA, Messenger