Cancer-associated fibroblasts promote enzalutamide resistance and PD-L1 expression in prostate cancer through CCL5-CCR5 paracrine axis
Description
Cancer associated fibroblasts (CAFs) have been shown to play a crucial role in regulating tumor chemotherapy and immunotherapy resistance. The therapeutic value of CAFs in prostate cancer has largely not been studied. Our research revealed that CAFs secrete CCL5, which promotes the upregulation of androgen receptor (AR) expression in prostate cancer cells, leading to resistance to enzalutamide therapy. Furthermore, CCL5 also enhances the expression of tumor programmed death-ligand 1 (PD-L1), resulting in immune escape. Mechanistically, CCL5 binds to its receptor, CC motif chemokine receptor 5 (CCR5), on prostate cancer cells and activates the AKT signaling pathway, leading to the upregulation of AR and PD-L1. The CCR5 antagonist maraviroc to inhibit the CAFs mediated CCL5 signaling pathway can effectively reduce the expression of AR and PD-L1, and improve the efficacy of enzalutamide. Together, CAFs can enhance the expression of AR and PD-L1 by paracrine CCL5 binding to CCR5 activated AKT pathway in prostate cancer, resulting in enzalutamide resistance and immune escape. And targeting CCL5-CCR5 communication as a promising treatment method to improve the effectiveness of enzalutamide.