CTL Attenuation Regulated by PS1 in Cancer-Associated Fibroblast

Objective:Cancer-associated fibroblasts (CAFs) were associated with tumor progression in the tumor microenvironment (TME). However, their immunosuppressive roles in protecting cancer cells from the attack by cytotoxic T lymphocytes (CTLs) are not fully clear. In this study, we investigated whether and how CAFs regulate tumor-infiltrating lymphocytes as well as their role in tumor immunosuppression. Methods:Eighty-three cases of ovarian cancer and 10 controls were analyzed for CAFs and CD8+ tumor-infiltrating lymphocytes by gene array and immunohistochemistry. We evaluated presenilin 1 (PS1) expression in CAFs, CTL penetration, tumor burden, dendritic cell function, and migration of tumor-infiltrating lymphocytes and their functionin vivoandin vitroafter silencing PS1. In addition, the pathway via which PS1 affects the TME was also evaluated. Results:PS1 was highly expressed in CAFs, and its silencing significantly promoted CD8+ CTL proliferation and penetration in multiple ovarian models (p< 0.05), resulting in tumor regression and growth inhibition. Interleukin (IL)-1 beta was identified as a major immune inhibitor in the TME, and it was significantly decreased after PS1 silencing (p< 0.05), which was regulated by the WNT/beta-catenin pathway. It was also showed that high expression of IL-1 beta in CAFs inhibits CTL penetration significantly (p< 0.05). Conclusion:Highly expressed PS1 in CAFs plays a crucial role in regulating tumor-infiltrating lymphocyte populations in the TME via the WNT/beta-catenin pathway. Targeting PS1 may retrieve functional CTLs in the TME and improve the efficacy of current immunotherapies.