Complement activation promoted by the lectin pathway mediates C3aR-dependent sarcoma progression and immunosuppression

Complement has emerged as a component of tumor-promoting inflammation. We conducted a systematic assessment of the role of complement activation and effector pathways in sarcomas. C3, MBL1/2 and C4 mice showed reduced susceptibility to 3-methylcholanthrene sarcomagenesis and transplanted sarcomas, whereas C1q and factor B deficiency had marginal effects. Complement 3a receptor (C3aR), but not C5aR1 and C5aR2, deficiency mirrored the phenotype of C3 mice. C3 and C3aR deficiency were associated with reduced accumulation and functional skewing of tumor-associated macrophages, increased T-cell activation and response to anti-PD-1 therapy. Transcriptional profiling of sarcoma-infiltrating macrophages and monocytes revealed the enrichment of the major histocompatibility complex II-dependent antigen presentation pathway in C3-deficient cells. In patients, C3aR expression correlated with a macrophage population signature, and C3-deficiency-associated signatures predicted better clinical outcome. These results suggest that the lectin pathway and C3a-C3aR axis are key components of complement and macrophage-mediated sarcoma promotion and immunosuppression.