{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Eto R"],"funding":["MEXT | Japan Society for the Promotion of Science","MEXT | Japan Society for the Promotion of Science (JSPS)","This study was also supported by Denka Company Limited"],"pagination":["1791-1801"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12690149"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["133(12)"],"pubmed_abstract":["<h4>Background</h4>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).<h4>Methods</h4>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.<h4>Results</h4>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<sup>+</sup> T cells and an increase in CD11b<sup>+</sup> 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<sup>+</sup> T cells was significantly increased in CCX168-treated groups, whereas CCX168 treatment resulted in a decrease in MDSCs.<h4>Conclusions</h4>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."],"journal":["British journal of cancer"],"pubmed_title":["Inhibition of C5a-C5aR1 axis suppresses tumour progression by enhancing antitumour immunity and chemotherapeutic effect in pancreatic ductal adenocarcinoma."],"pmcid":["PMC12690149"],"funding_grant_id":["24K11907","23K08207"],"pubmed_authors":["Eto R","Suzuki D","Takano S","Zhou D","Suzuki K","Takayashiki T","Ohtsuka M","Sakai N"],"additional_accession":[]},"is_claimable":false,"name":"Inhibition of C5a-C5aR1 axis suppresses tumour progression by enhancing antitumour immunity and chemotherapeutic effect in pancreatic ductal adenocarcinoma.","description":"<h4>Background</h4>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).<h4>Methods</h4>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.<h4>Results</h4>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<sup>+</sup> T cells and an increase in CD11b<sup>+</sup> 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<sup>+</sup> T cells was significantly increased in CCX168-treated groups, whereas CCX168 treatment resulted in a decrease in MDSCs.<h4>Conclusions</h4>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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Dec","modification":"2026-06-06T00:30:48.963Z","creation":"2026-05-24T03:11:48.38Z"},"accession":"S-EPMC12690149","cross_references":{"pubmed":["41044172"],"doi":["10.1038/s41416-025-03185-0"]}}