Inhibition of C5a-C5aR1 axis suppresses tumour progression by enhancing antitumour immunity and chemotherapeutic effect in pancreatic ductal adenocarcinoma.

BACKGROUND: Complement factors regulate tumour immunity in the tumour microenvironment (TME). We investigated the functions of complement 5a (C5a) and its receptors, C5aR1 and C5aR2, in forming the C5a-C5aR1 and C5a-C5aR2 signaling axes in the immune TME of pancreatic ductal adenocarcinoma (PDAC). METHODS: C5a, C5aR1 and C5aR2 were assessed in cancer cell cytoplasmic (c-) and stromal (s-) expressions in resected PDAC tissues. In vitro assays were conducted to examine endogenous C5aR1 functions in PDAC cells, and orthotopic transplantation was performed in a preclinical study. RESULTS: In immunohistochemistry, High C5a-C5aR1 c-axis was correlated with poor prognosis and High C5a-C5aR1 s-axis was associated with a decrease in CD8(+) T cells and an increase in CD11b(+) MDSCs. C5aR1 knockdown and CCX168, the specific C5aR1 inhibitor, impaired proliferation and the activation of the PI3K/mTOR pathway, and enhanced gemcitabine sensitivity by increasing apoptosis. The combination of CCX168 and gemcitabine/nab-paclitaxel demonstrated a significant reduction in tumour volume. The number of CD8(+) T cells was significantly increased in CCX168-treated groups, whereas CCX168 treatment resulted in a decrease in MDSCs. CONCLUSIONS: The C5a-C5aR1 axis may exert a tumour-promoting effect on the TME in PDAC. CCX168 appears to modulate antitumour immunity, thereby warranting future complement-based immunomodulation therapies for PDAC.