Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy

Summary Complement is a critical component of humoral immunity implicated in cancer development; however, its biological contributions to tumorigenesis remain poorly understood. Using the K14-HPV16 transgenic mouse model of squamous carcinogenesis, we report that urokinase (uPA) + macrophages regulate C3-independent release of C5a during premalignant progression, which in turn regulates protumorigenic properties of C5aR1 + mast cells and macrophages, including suppression of CD8 + T cell cytotoxicity. Therapeutic inhibition of C5aR1 via the peptide antagonist PMX-53 improved efficacy of paclitaxel chemotherapy associated with increased presence and cytotoxic properties of CXCR3 + effector memory CD8 + T cells in carcinomas, dependent on both macrophage transcriptional programming and IFNγ. Together, these data identify C5aR1-dependent signaling as an important immunomodulatory program in neoplastic tissue tractable for combinatorial cancer immunotherapy.