Complement C3aR loss drives colorectal cancer by modulating gut microbiota

Several lines of evidence suggest that inflammation plays a pivotal role in the development and progression of colorectal cancer (CRC) and can be unleashed by the loss of innate immunosurveillance. The complement system is a central component of immunity and is essential for intestinal homeostasis. Emerging evidence suggests that complement dysregulation is involved in the development and progression of CRC. Here we show for the first time that methylation of the complement anaphylatoxin C3a receptor (c3aR1) in CRC patients results in decreased overall survival and events-free survival. Based on our clinical findings, we ablated c3ar1 in the spontaneous APCMin mouse model of intestinal tumorigenesis. Loss of C3aR in this model resulted in a shift of tumorigenesis from the small intestine to the colon, therefore more closely mirroring human CRC. By performing microbiota sequencing and fecal microbiota transplantation (FMT) experiments, we found that loss of C3aR resulted in the establishment of a pro-inflammatory microbial flora, which fostered strong Th1/Th17 cell inflammation. Our findings highlight a previously unrecognized oncosuppressive role for C3aR in CRC that could be exploited as a biomarker or for therapeutic intervention.