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