Cancer-associated fibroblast subtypes differentially modulate natural killer cells in cancer

Natural killer (NK) cells are cytotoxic innate lymphoid cells which directly kill tumor cells, thus represent an attractive target for immunotherapy. However, NK cells face immunosuppression in the tumor microenvironment (TME), rendering them dysfunctional. While cancer-associated fibroblasts (CAFs) represent an abundant, heterogeneous component of pancreatic ductal adenocarcinoma (PDAC), their interplay with NK cells is largely understudied. Analyzing human samples and employing mouse models of PDAC and functional assays, we observed that intratumoral NK cells are immature, and TGF-β driven myofibroblastic (my)CAFs are strong NK suppressors, in contrast to inflammatory (i)CAF. Furthermore, myCAF-enriched tumor areas excluded NK cells, consistent with their reduced capacity to attract NK cells. Pancreatic CAFs in general reduced NK cell cytotoxicity by direct contact and via soluble factors, including prostaglandin E2 (PGE2). This work reveals distinct and overlapping roles of CAF subpopulations on NK cell functions, suggesting that overcoming CAF-imposed barriers to NK cytotoxicity and tumor infiltration is essential to unleash their anti-tumoral properties.