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

1. Nat Commun. 2018 Feb 28;9(1):873. doi: 10.1038/s41467-018-03225-9. Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype. Chen D(1), Xie J(1), Fiskesund R(1), Dong W(1), Liang X(1), Lv J(1), Jin X(1), Liu J(1), Mo S(1), Zhang T(1), Cheng F(1), Zhou Y(1), Zhang H(2), Tang K(2), Ma J(2), Liu Y(1)(3), Huang B(4)(5)(6). Author information: (1)Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005, China. (2)Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. (3)Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, 100005, China. (4)Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005, China. tjhuangbo@hotmail.com. (5)Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. tjhuangbo@hotmail.com. (6)Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, 100005, China. tjhuangbo@hotmail.com. Erratum in Nat Commun. 2018 May 1;9(1):1808. doi: 10.1038/s41467-018-04169-w. 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. DOI: 10.1038/s41467-018-03225-9 PMCID: PMC5830447 PMID: 29491374 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing financial interests.