Synergistic Anticancer Effects of COL6A1 Downregulation and the PD1 Inhibitor Pembrolizumab in Bladder Cancer

Immunotherapy has shown remarkable efficacy in treatment of bladder cancer. Collagen type VI alpha 1 (COL6A1) is found to be linked to response to immunotherapy of programmed cell death protein 1 (PD1) checkpoint inhibitors. This study elucidated the critical role of COL6A1 in regulating immune escape and response to the PD1 inhibitor pembrolizumab. Expression analysis was performed by quantitative PCR, western blotting, and immunohistochemistry. Cell in vitro functions were evaluated by detecting cell proliferation, invasion, migration, and apoptosis. Xenograft assays were used to define the role of COL6A1 in vivo. CD8⁺ T cells were co-cultured with treated T24 and J82 cells to analyze the impact of COL6A1 knockdown and pembrolizumab on cell immune response. High COL6A1 expression was observed in bladder cancer tissues and cells. COL6A1 downregulation inhibited bladder cancer cell proliferation, invasion, and migration and induced cell apoptosis. Moreover, COL6A1 knockdown reduced the apoptosis of CD8⁺ T cells and reduced the expression of PD-L1. Knockdown of COL6A1 also suppressed bladder cancer tumor growth in vivo. Pembrolizumab inhibited bladder cancer cell proliferation, invasion, and migration and attenuated CD8⁺ cell apoptosis. Importantly, COL6A1 downregulation enhanced the therapeutic efficacy of pembrolizumab on bladder cancer cell malignant progression and immune escape. Combination of COL6A1 downregulation and pembrolizumab synergistically suppressed bladder cancer cell growth and metastasis, providing the possibility of inhibiting bladder cancer progression.