Abstract 5833: Crosstalk between cancer-associated fibroblasts and CD8 T cells leads to improved T cell activation in head and neck cancer

Abstract

Abstract Cancer-associated fibroblasts (CAFs) have been shown to modulate immune responses in the tumor microenvironment (TME), however, the extensive heterogeneity of these cells has precluded rigorous understanding of their immunoregulatory role in the head and neck TME. To gain a better understanding of the relationship between CAFs 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. Utilizing in vitro co-culture assays with primary human CD8 T cells, 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 CAFs (tsCAFs). In efforts to elucidate the mechanism behind this pro-inflammatory function, we determined that tsCAFs secrete a heat-sensitive small molecule/s in order to alter CD8 T cell behavior. However, tsCAFs will only secrete this factor in the presence of activated T cells demonstrating crosstalk between T cells and CAFs in the head and neck TME. This pro-inflammatory crosstalk between CAFs and T cells represents a novel finding that further contributes to the idea of immunoregulatory pleiotropy among CAFs. Accordingly, our findings highlight the functional importance of distinct CAF subsets in modulating the immunoregulatory milieu of human HNSCC and warrant more extensive characterization of CAF-T cell interactions in human squamous cell carcinoma. Citation Format: Diana Graves, Aleksandar Obradovic, Henry Schares, Michael Korrer, Brian Bachmann, Young Kim, Ben Park, Paula Hurley. Crosstalk between cancer-associated fibroblasts and CD8 T cells leads to improved T cell activation in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5833.