Immunomodulatory cancer-associated fibroblasts influence Treg cell dynamics in lung cancer 2712

Abstract Description The tumor microenvironment (TME) is a highly complex multicellular system and has been shown to play a fundamental role in dictating tumorigenesis. High expression of regulatory surface molecules, cytokines, and chemokines in fibroblast niches within lung tumor stroma, paired with their colocalization with Treg cells, suggests cancer-associated fibroblast (CAF) niches may alter the functional response of Treg cells and influence anti-tumor immunity. Here, utilizing a transcriptomic approach, we have uncovered a distinct CAF population – which we term “imCAFs” – that is predominantly localized to tumor-derived tissue samples and is enriched for immunomodulatory gene signatures, T cell ligands, and chemoattractants. This population expresses a unique set of cell surface molecules that permit their identification and isolation from lung tumor tissue. Interestingly, CXCL9, a well-established T cell chemoattractant, was among the top differentially expressed genes in the imCAF population. We were able to demonstrate that TME Treg cells preferentially migrate to CXCL9 gradients, and colocalize with CXCL9-producing imCAFs in lung tumors. CXCL9-producing imCAFs attract a unique subset of Treg cells that highly upregulate the CXCL9 receptor, CXCR3. This subset of Treg cells is functionally distinct from CXCR3-negative Treg cells. Our analyses suggest that imCAFs play a critical role in dictating the recruitment and function of a specific subset of Treg cells to the TME in lung tumors. Funding Sources Supported by NIH/NHLBI R01HL148718; NIH/NIAID T32AI106711. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)