Manipulation of the Complement Pathway to Increase Radiation Sensitivity and Immune Response

One of the research directions of my laboratory is identifying targets that act both to protect against radiation induced normal tissue toxicity but also are able to sensitise tumours to radiation. In our screen for such agents, we found that targeting the complement pathway at the level of C5aR1 can improve radiation response in colorectal cancer models while also reducing radiation-induced small bowel toxicity. The complement system is an innate immunity pathway composed of soluble and cell surface proteins. Proteolytic cleavage of complement components leads to their activation and the formation of downstream effectors. Complement cleavage products signal through cell surface receptors such as C3aR1 and C5aR1. C5aR1 is the main receptor for C5a, which is considered the most potent anaphylatoxin of the complement cascade. To date, very few molecules have been approved that can modify the radiation response of tumors and only one molecule that has been approved to protect against normal tissue damage-amifostine. The innovation in this proposal is based on the identification of a single molecule C5aR1, which can increase therapeutic index by protecting normal tissue from radiation induced damage and at the same time radiosensitising tumours.