Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD-L1 expression by C5a.

The treatment of castration-resistant prostate cancer (CRPC) is a urological issue. Recent studies have revealed cancer promotion via the C5a-C5a receptor (C5aR) system. To establish a new therapeutic target for CRPC, we investigated an association of the system with CRPC progression and evasion from the antitumor immune responses. C5aR and PD-L1 were immunostained in the prostate cancer (PC) tissues. The relationship of PC C5aR expression to clinicopathological parameters was analyzed. CRPC cell lines were examined for C5aR expression by real-time reverse transcription polymerase chain reaction, immunoblotting, and flow cytometry. C5a effects were examined on CRPC cell glutamine consumption, proliferation, invasion, and PD-L1 expression. PC cells expressed C5aR in 83 of the 161 patients (52%) and in three of the six CRPC patients. Basal cells, but not luminal cells, of noncancerous prostate glands expressed C5aR. Three CRPC cell lines expressed C5aR. C5a increased CRPC cell glutamine consumption 2.1-fold, proliferation 1.3-1.6-fold, and invasion 2-3-fold in a C5a-concentration and a C5aR-dependent manner. High expression of C5aR did not relate to the PC patients' clinical parameters but the PD-L1-positive rate was higher in the C5aR high-expression patients (37.5%) compared to low- or no expression patients (17.8%), and double-positive PC cells were present. C5a increased CRPC cell PD-L1 production 1.4-fold and cell-surface expression 2.6-fold. C5aR expression of PC cells in patients' tissues and C5a augmentation of C5aR-dependent CRPC proliferation, invasion, and PD-L1 expression suggested participation of the C5a-C5aR system in CRPC promotion and evasion from antitumor immune responses. Targeting this signaling pathway may provide a useful therapeutic option for CRPC.