Unveiling the Molecular Mechanisms Driving the Capsaicin-Induced Immunomodulatory Effects on PD-L1 Expression in Bladder and Renal Cancer Cell Lines

SIMPLE SUMMARY: Over time, capsaicin (CPS) has been considered both a potential anti-cancer and pro-cancer molecule. Hence, the diversity of CPS functioning has already been established. Now, exploration of its application with immunotherapies might open up a new avenue in cancer therapy. Herein, the application of CPS as an immunoadjuvant to overcome the tumor’s immune-escaping mechanisms or to increase immune checkpoint therapy has been approached. In bladder cancer, the interaction of CPS with its receptor TRPV1 increases PD-L1 expression, promoting a tumorigenic effect and also providing a target for anti-PD-1/PD-L1 immunotherapy. On the contrary, in renal cell carcinoma, CPS downregulates PD-L1 expression in a TRPV1-independent manner, suggesting a potential application of CPS as an immune-adjuvant in this type of cancer. ABSTRACT: The blockade of the PD-L1/PD-1 immune checkpoint has promising efficacy in cancer treatment. However, few patients with bladder cancer (BC) or renal cell carcinoma (RCC) respond to this approach. Thus, it is important to implement a strategy to stimulate the immune anti-tumor response. In this scenario, our study evaluated the effects of a low capsaicin (CPS) dose in BC and RCC cell lines. Western blot, qRT-PCR and confocal microscopy were used to assess PD-L1 mRNA and protein expression. Alterations to the cellular oxidative status and changes to the antioxidant NME4 levels, mRNA modulation of cytokines, growth factors, transcriptional factors and oncogene, and the activation of Stat1/Stat3 pathways were examined using Western blot, cytofluorimetry and qRT-PCR profiling assays. In BC, CPS triggers an altered stress oxidative-mediated DNA double-strand break response and increases the PD-L1 expression. On the contrary, in RCC, CPS, by stimulating an efficient DNA damage repair response, thus triggering protein carbonylation, reduces the PD-L1 expression. Overall, our results show that CPS mediates a multi-faceted approach. In modulating PD-L1 expression, there is a rationale for CPS exploitation as a stimulus that increases BC cells’ response to immunotherapy or as an immune adjuvant to improve the efficacy of the conventional therapy in RCC patients.