Abstract
Background: Tumor immune escape is a critical step in tumor progression. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) express abundant PD-L1 and suppress the functions of CD8+T cells, enablingd immune escape. CD248 is a candidate bioindicator for CAFs associated with non-small cell lung cancer (NSCLC), although its involvement in immune escape is not known. Methods: Fibroblasts were isolated from tumor and normal lung tissues from patients. We detected the expression of CD248 and PD-L1 on CAFs. Then, the influence of CAFs inhibited the function of CD8+T cells promoting NSCLC immune escape was assessed in vivo and in vitro. Finally, explored the mechanisms of which CD248 induced PD-L1 expression on CAFs. Results: Herein, we demonstrated that CD248 increased CAF PD-L1 levels, inhibiting CD8+T-cell function, thereby promoting NSCLC cell invasion and migration. CD248-induced FAK/Src/JNK/c-Jun axis activation promoted PD-L1 expression on CAFs. In tumor-bearing mice, lung tumors grew significantly slower, and the amount of granzyme B+CD8+T cells was greater in fibroblast-specific CD248 gene knockout mice than in wild-type mice. More importantly, we found that tislelizumab efficiency was improved in CD248 gene knockout mice. Conclusion: Our findings demonstrate that CD248 activates FAK/Src/JNK/c-Jun, thereby inducing PD-L1 expression on CAFs, which promotes NSCLC immune escape.