Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modulating tumor-associated macrophages

Abstract

Complement aids in the construction of an immunosuppressive tumor microenvironment (TME). Tumor cell-derived C3 has been previously reported, but whether and how it acts on antitumor immunity remains to be elucidated. Here, we describe a mechanism for tumor cell-derived C3 in suppressing antitumor immunity. Tumor cell-derived C3 was activated intracellularly, which results in generation of C3a. C3a modulated tumor-associated macrophages (TAMs) via C3a-C3aR-PI3Kγ signaling, thereby repressing antitumor immunity. Deletion of C3 in tumor cells that had high C3 expression enhanced efficacy of anti-PD-L1 treatment. Collectively, our results suggest tumor cell derived C3 may be a useful target for cancer immunotherapy and that targeting C3 in tumor cells may enhance antitumor immunity.