Zha et al. showed that activation of complement factor C3 within tumor cells promoted an immunosuppressive TME by mediating the accumulation of TAMs and promoting their polarization towards an M2 (pro-tumor) phenotype. M2 polarization was induced by C3a binding to C3aR on TAMs, thereby activating PI3Kγ signaling and subsequent Akt phosphorylation. Deletion of C3 in various murine tumor models reduced tumor infiltration by TAMs, promoted M1 polarization, increased CD8+ T cell infiltration and proliferation, and slightly delayed tumor growth. Survival was significantly improved in conjunction with anti-PD-L1.
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-PI3Kgamma 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.
Author Info: (1) Institute of Cancer, Xinqiao Hospital, Third Military Medical University. (2) Xinqiao Hospital, Institute of Cancer. (3) Institute of Cancer, Xinqiao Hospital, Third Military M
Author Info: (1) Institute of Cancer, Xinqiao Hospital, Third Military Medical University. (2) Xinqiao Hospital, Institute of Cancer. (3) Institute of Cancer, Xinqiao Hospital, Third Military Medical University. (4) Xinqiao Hospital, Third Military Medical University, Institute for Cancer Research in People's Liberation Army. (5) Institute of Cancer, Xinqiao Hospital, Third Military Medical University. (6) Institute of Immunology, Third Military Medical University. (7) Institute of Cancer, Xinqiao Hospital, Third Military Medical University. (8) Third Military Medical University, Institute of Cancer, Xinqiao Hospital. (9) Institute of Cancer, Xinqiao Hospital, Third Military Medical University. (10) Institute of Cancer, Xinqiao Hospital, Third Military Medical University. (11) Institute of Tropical Medicine, Third Military Medical University. (12) Institute of Immunology, Third Military Medical University. (13) Institute of Cancer, Xinqiao Hospital, Third Military Medical University. (14) Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. (15) Institute of Cancer, Xinqiao Hospital, Third Military Medical University. (16) Institute of Cancer, Xinqiao Hospital, Third Military Medical University bo.zhu@tmmu.edu.cn.
