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Cancer Immunology Research

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Research Article

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

Haoran Zha, Xinxin Wang, Ying Zhu, Dian-gang Chen, Xiao Han, Fei Yang, Jianbao Gao, Chunyan Hu, Chi Shu, Yi Feng, Yulong Tan, Jinyu Zhang, Yongsheng Li, Yisong Y Wan, Bo Guo and Bo Zhu
Haoran Zha
Institute of Cancer, Xinqiao Hospital, Third Military Medical University
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Xinxin Wang
Xinqiao Hospital, Institute of Cancer
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Ying Zhu
Institute of Cancer, Xinqiao Hospital, Third Military Medical University
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Dian-gang Chen
Xinqiao Hospital, Third Military Medical University, Institute for Cancer Research in People's Liberation Army
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Xiao Han
Institute of Cancer, Xinqiao Hospital, Third Military Medical University
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Fei Yang
Institute of Immunology, Third Military Medical University
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Jianbao Gao
Institute of Cancer, Xinqiao Hospital, Third Military Medical University
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  • ORCID record for Jianbao Gao
Chunyan Hu
Third Military Medical University, Institute of Cancer, Xinqiao Hospital
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Chi Shu
Institute of Cancer, Xinqiao Hospital, Third Military Medical University
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Yi Feng
Institute of Cancer, Xinqiao Hospital, Third Military Medical University
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Yulong Tan
Institute of Tropical Medicine, Third Military Medical University
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Jinyu Zhang
Institute of Immunology, Third Military Medical University
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Yongsheng Li
Institute of Cancer, Xinqiao Hospital, Third Military Medical University
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Yisong Y Wan
Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
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Bo Guo
Institute of Cancer, Xinqiao Hospital, Third Military Medical University
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Bo Zhu
Institute of Cancer, Xinqiao Hospital, Third Military Medical University
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  • For correspondence: bo.zhu@tmmu.edu.cn
DOI: 10.1158/2326-6066.CIR-18-0272
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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.

  • Received April 23, 2018.
  • Revision received August 27, 2018.
  • Accepted November 29, 2018.
  • Copyright ©2018, American Association for Cancer Research.

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Published OnlineFirst December 4, 2018
doi: 10.1158/2326-6066.CIR-18-0272

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Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modulating tumor-associated macrophages
Haoran Zha, Xinxin Wang, Ying Zhu, Dian-gang Chen, Xiao Han, Fei Yang, Jianbao Gao, Chunyan Hu, Chi Shu, Yi Feng, Yulong Tan, Jinyu Zhang, Yongsheng Li, Yisong Y Wan, Bo Guo and Bo Zhu
Cancer Immunol Res December 4 2018 DOI: 10.1158/2326-6066.CIR-18-0272

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Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modulating tumor-associated macrophages
Haoran Zha, Xinxin Wang, Ying Zhu, Dian-gang Chen, Xiao Han, Fei Yang, Jianbao Gao, Chunyan Hu, Chi Shu, Yi Feng, Yulong Tan, Jinyu Zhang, Yongsheng Li, Yisong Y Wan, Bo Guo and Bo Zhu
Cancer Immunol Res December 4 2018 DOI: 10.1158/2326-6066.CIR-18-0272
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