RESUMEN
Cancer-associated fibroblasts (CAFs) have been shown to play a key role in prostate cancer treatment resistance, but the role of CAFs in the initial course of enzalutamide therapy for prostate cancer remains unclear. 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 the receptor 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. This study highlights a promising therapeutic approach targeting the CCL5-CCR5 signaling pathway to improve the effectiveness of enzalutamide.
RESUMEN
BACKGROUND: Although clear cell renal cell carcinoma (ccRCC) is well known as a highly immunogenic tumor, only a small subset of patients could benefit from current immunotherapy, which might be due to the heterogeneity of immune microenvironment in ccRCC. So, it is meaningful to explore novel immunotherapy or combination therapy for improving therapeutic efficacy. HHLA2, a newly discovered B7 family member, is prevalently expressed in numerous tumors, including ccRCC. This study aimed to investigate the prognostic impact of HHLA2/PD-L1 co-expression and its relationship with tumor-infiltrating lymphocytes (TILs). METHODS: The expression levels of HHLA2, PD-L1, CD8, and CD4 in cancer tissues from cases (206 in the training cohort and 197 in the validation cohort) with surgically resectable primary ccRCC were evaluated by immunohistochemistry. RESULTS: The positive rates of HHLA2 were much higher than those of PD-L1 in ccRCC tissues. HHLA2-positive expression was significantly associated with necrosis, microvascular invasion, advanced Fuhrman nuclear, and TNM stage and indicated a shorter progression-free survival (PFS) and overall survival (OS) in both cohorts. Moreover, patients with HHLA2/PD-L1 co-expression suffered the highest risk of disease progression and death by a significant margin. Besides, HHLA2/PD-L1 co-expression was significantly associated with a high density of CD8+ and CD4+ TILs. Notably, a new immune classification, based on HHLA2/PD-L1 co-expression and TILs, successfully stratified PFS and OS, especially in patients with TILs positivity. CONCLUSIONS: The expression of HHLA2 is more frequent than PD-L1 in ccRCC. HHLA2/PD-L1 co-expression had an adverse impact on the prognoses of patients with ccRCC; this finding provides a rationale for combination immunotherapy with anti-HHLA2 and PD-L1 blockage for patients with ccRCC in the future.
