Matrix reboot: IL-17 signals CAFs to create a second tumor T cell checkpoint

Abstract

Excessive collagen deposition by fibroblasts surrounding some tumors has seriously limited the efficacy of checkpoint inhibitor therapies. Chen et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20210693) show that IL-17 promotes collagen deposition by cancer-associated fibroblasts, enhancing immune exclusion of tumors, and that targeting IL-17-triggered HIF1α expression can reverse matrix mediated immune exclusion.

Insights from Mandy J. McGeachy.

IL-17 enhances collagen deposition through HIF1α expression in CAFs. Checkpoint inhibitor therapy (anti–PD-L1) in mice with established tumors activates T cells and increases IL-17 production, leading to increased collagen deposition and inhibition of activated CD8⁺ T cell access to the tumor, which continues to grow. Deletion of IL-17 receptor on CAFs or blockade of IL-17 induction of HIF1a with an Act1:Hif1a aptamer reduces collagen deposition around the established tumor to allow anti–PD-L1 activated T cells to enter and restrict tumor growth. Figure created with Biorender.com.