Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy

Abstract The role of inflammation in colorectal cancer (CRC) development and response to therapy is highly debated. While a known driver CRC, inflammatory immune infiltrates are positive prognostic factor CRC as can enhance checkpoint blockade (ICB) therapy. Yet, the majority poorly infiltrated even presence an infiltrate half these cancers become refractory ICB. Therefore, there need identify mechanisms establish supportive inflammation. We have previously reported that certain patients with down-regulate receptor for complement anaphylatoxin C3a (C3aR). system first line defense against pathogens central component response. Emerging evidence suggests C3aR may play intestinal homeostasis. However, date, it unknown how affects Using our novel mouse model (APCMin/+/C3aR−/−) we showed loss results enhanced infiltration typically “cold” tumors changes microbiota. Similarly, found down-regulation correlates specific tumor-infiltrating cells. Notably, when treated a-PD1, APCMin/+/C3aR−/− mice significant reduction tumors, suggesting unleashes colon microbiota-mediated be exploited therapeutic purposes. Our findings reveal act unrecognized antitumor immunity inhibition used overcome ICB resistance larger group patients. This project was supported part by NIH P20 GM120475 (core facility) at MUSC Digestive Disease Research Core Center.