Immunostimulatory Head and Neck Cancer-associated Fibroblasts Promote T Cell Activation via Prostaglandin E2 and Predict Immunotherapy Response

Abstract

The extensive heterogeneity of cancer-associated fibroblasts (CAF) has precluded rigorous understanding of their immunoregulatory role in the head and neck tumor microenvironment (TME). To investigate the relationship between CAF and the immune environment in head and neck cancer, we leveraged protein activity inference tools to analyze single-cell RNA sequencing of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients pre- and post-treatment with the αPD-1 therapy, nivolumab. From this analysis, we identified a novel CAF population predictive of patient response to αPD-1 therapy. Upon further investigation, we discovered that this novel CAF population was able to elicit features associated with enhanced CD8+ T cell function, namely the reduction of PD-1+TIM-3+ exhaustive phenotypes and induction of CD103+NKG2A+ tissue-resident memory phenotypes and cytotoxicity. Due to their unique ability to stimulate T cells in this manner, we termed this novel CAF population T cell-stimulating CAF (tsCAF). In efforts to elucidate the mechanism behind this pro-inflammatory function, we determined that tsCAF secrete prostaglandin E2 to alter CD8+ T cell behavior. However, tsCAF will only secrete PGE2 following T cell-mediated NFkB activation in tsCAF demonstrating crosstalk between T cells and CAF in the head and neck TME. This pro-inflammatory crosstalk between CAF and T cells further contributes to the idea of immunoregulatory pleiotropy among CAF and highlights the importance of distinct CAF subsets in regulating immunotherapy response in human HNSCC.