Intracellular Activation of Complement C3 Leads to PD-L1 Antibody Treatment Resistance by Modulating Tumor-Associated Macrophages

Haoran Zha; Xinxin Wang; Ying Zhu; Diangang Chen; Xiao Han; Fei Yang; Jianbao Gao; Chunyan Hu; Chi Shu; Yi Feng; Yulong Tan; Jinyu Zhang; Yongsheng Li; Yisong Y Wan; Bo Guo; Bo Zhu

doi:10.1158/2326-6066.CIR-18-0272

Intracellular Activation of Complement C3 Leads to PD-L1 Antibody Treatment Resistance by Modulating Tumor-Associated Macrophages

Cancer Immunol Res. 2019 Feb;7(2):193-207. doi: 10.1158/2326-6066.CIR-18-0272. Epub 2018 Dec 4.

Authors

Haoran Zha^{1

2

3}, Xinxin Wang^{1

2}, Ying Zhu^{1

2}, Diangang Chen^{1

2}, Xiao Han^{1

2}, Fei Yang⁴, Jianbao Gao^{1

2}, Chunyan Hu^{1

2}, Chi Shu^{1

2}, Yi Feng^{1

2}, Yulong Tan⁵, Jinyu Zhang⁴, Yongsheng Li⁶, Yisong Y Wan⁷, Bo Guo⁸, Bo Zhu^{9

2}

Affiliations

¹ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China.
² Chongqing Key Laboratory of Immunotherapy, Chongqing, P.R. China.
³ Department of Oncology, The General Hospital of the PLA Rocket Force, Beijing, P.R. China.
⁴ Department of Immunology, Third Military Medical University, Chongqing, P.R. China.
⁵ Institute of Tropical Medicine, Third Military Medical University, Chongqing, P.R. China.
⁶ Clinical Medicine Research Center and Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China.
⁷ Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Centre, University of North Carolina at Chapel Hill, Chapel Hill, North California.
⁸ Maternal and Child Health Research Institute, Baoan Women's and Children's Hospital, Jinan University, Shenzhen, P.R. China. [email protected] [email protected].
⁹ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China. [email protected] [email protected].

PMID: 30514794
DOI: 10.1158/2326-6066.CIR-18-0272

Abstract

Complement aids in the construction of an immunosuppressive tumor microenvironment. 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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Immunological / pharmacology*
B7-H1 Antigen / antagonists & inhibitors*
B7-H1 Antigen / metabolism
Class Ib Phosphatidylinositol 3-Kinase / metabolism
Complement Activation / immunology*
Complement C3 / immunology*
Disease Models, Animal
Female
Humans
Immunomodulation
Immunotherapy
Macrophages / immunology*
Macrophages / metabolism
Melanoma, Experimental
Mice
Neoplasms / immunology*
Neoplasms / metabolism
Neoplasms / pathology
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism
T-Lymphocyte Subsets / pathology
Tumor Microenvironment / immunology

Substances

Antineoplastic Agents, Immunological
B7-H1 Antigen
CD274 protein, human
Complement C3
Class Ib Phosphatidylinositol 3-Kinase
PIK3CG protein, human