Cisplatin remodels the tumor immune microenvironment via the transcription factor EB in ovarian cancer

Abstract

The mortality rate of ovarian cancer (OC) remains the highest among all gynecological malignancies. Platinum-based chemotherapies are effective in treating most OC cases. However, chemoresistance is still a major challenge for successful OC treatments. Emerging evidence has highlighted that the modulation of the tumor immune microenvironment is involved in chemoresistance, but the mechanism remains unclear. This study aimed to investigate whether resistance to cisplatin (CDDP), the standard treatment for OC, is due to the remodeling of the tumor immune microenvironment by the transcription factor EB (TFEB). We hypothesized that TFEB is not essential for tumor survival but is associated with CDDP resistance. We collected 20 tissue samples of OC patients who had not undergone chemotherapy or radiotherapy prior to surgery. We cultured OC cell lines and performed cell transfection and assays as well as analytical, fluorescence microscopy, and immunohistochemical techniques to explore a novel function of TFEB in remodeling the tumor immune microenvironment in OC. We found a positive correlation between TFEB and programmed cell death-ligand 1 (PD-L1), PD-L2, and HLA-A expression in OC cells and tissues. We also found that CDDP treatment induced TFEB nuclear translocation, thus increasing PD-L1 and PD-L2 expression to foster an immunosuppressive tumor microenvironment, which mediates tumor immune evasion and drug resistance. Interestingly, TFEB also regulated HLA-A expression, which increases the tumor immunogenicity of OC. Finally, in a syngenic murine model of OC, we observed the therapeutic benefit of CDDP plus programmed cell death-1 (PD-1) inhibitor, which enhanced the cytolytic activity of CD8⁺ T cells and inhibited tumor growth. Our study illustrates the important role of TFEB in regulating the tumor immune microenvironment in OC.