Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype

Degao Chen, Jing Xie, Roland Fiskesund, Wenqian Dong, Xiaoyu Liang, Jiadi Lv, Xun Jin, Jinyan Liu, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Huafeng Zhang, Ke Tang, Jingwei Ma, Yuying Liu and Bo Huang ()
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Degao Chen: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Jing Xie: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Roland Fiskesund: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Wenqian Dong: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Xiaoyu Liang: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Jiadi Lv: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Xun Jin: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Jinyan Liu: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Siqi Mo: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Tianzhen Zhang: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Feiran Cheng: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Yabo Zhou: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Huafeng Zhang: Huazhong University of Science and Technology
Ke Tang: Huazhong University of Science and Technology
Jingwei Ma: Huazhong University of Science and Technology
Yuying Liu: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Bo Huang: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca2+ release via the lysosomal Ca2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca2+ activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality.

Date: 2018
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DOI: 10.1038/s41467-018-03225-9

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