FAP upregulates PD-L1 expression in cancer-associated fibroblasts to exacerbate T cells dysfunction and suppress anti-tumor immunity

Abstract

FAP-positive cancer-associated fibroblasts (CAFs), recognized as a critical subset of CAFs, have been implicated in fostering an immunosuppressive tumor microenvironment in various cancers. However, their potential mechanisms of immunosuppression, particularly in modulating T cells, remain elusive. In this study, multiple internal cohorts consisting of 328 patients as well as 5 external cohorts were integrated to delineate the association between unfavorable prognosis or therapeutic resistance and FAP⁺ CAFs in gastric cancer patients. Subsequently, using in vivo mice models and in vitro co-culture system, we found that elevated infiltration levels of FAP⁺ CAF exacerbated immunosuppression in the tumor microenvironment by facilitating CD8⁺ T cells dysfunction. Mechanistically, FAP impeded the degradation of STAT1 protein in CAFs, thereby sustaining PD-L1 transcription and fostering T cell exhaustion. Treatment with PD-L1 neutralizing antibodies effectively attenuated FAP-mediated immunosuppression, restoring anti-tumor immunity of T cells. Overall, our findings underscore the vital role of FAP⁺ CAFs in directly suppressing T cell-mediated anti-tumor immunity via PD-L1 upregulation, paving the way for the development of FAP-targeted therapies in clinical settings.

Keywords: Cancer-associated fibroblasts; FAP; Gastric cancer; Immunosuppression; PD-L1; T cells dysfunction.