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.