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.