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

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-?B, 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.

SUBMITTER: Chen D

PROVIDER: S-EPMC5830447 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Chen Degao D Xie Jing J Fiskesund Roland R Dong Wenqian W Liang Xiaoyu X Lv Jiadi J Jin Xun X Liu Jinyan J Mo Siqi S Zhang Tianzhen T Cheng Feiran F Zhou Yabo Y Zhang Huafeng H Tang Ke K Ma Jingwei J Liu Yuying Y Huang Bo B

Nature communications 20180228 1

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 Ca<sup>2+</sup> release via the lysosomal Ca<sup>2+</sup> channel mucolipin-1 (Mcoln1), ...[more]

PMID: 29491374

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Project description:BackgroundGlioblastoma multiforme (GBM) induces tumor immunosuppression through interacting with tumor-infiltrating microglia or macrophages (TAMs) with an unclear pathogenesis. Enhancer of zeste homolog 2 (EZH2) is abundant in GBM samples and cell lines and is involved in GBM proliferation, cell cycle, and invasion, whereas its association with innate immune response is not yet reported. Herein, the aim of this study was to investigate the role of EZH2 in GBM immune.MethodsCo-culturing models of human/murine GBM cells with PBMC-derived macrophages/primary microglia were employed. EZH2 mRNAs and function were suppressed by siEZH2 and DZNep. Real-time PCR and flow cytometry were used to determine levels of microglia/macrophages markers. The fluorescence-labeled latex beads and flow cytometry were utilized to evaluate phagocytic abilities of microglia. CCK8 assay was performed to assess microglia proliferation.ResultsEZH2 inhibition led to significant reduction of TGF?1-3 and IL10 and elevation of IL1? and IL6 in human and murine GBM cells. More importantly, EZH2 suppression in GBM cells resulted in significant increase of M1 markers (TNF? and iNOS) and decrease of a pool of M2 markers in murine microglia. The proportion of CD206+ cells was decreased in PBMC-derived macrophages as co-incubated with EZH2-inhibited GBM cells. Functional researches showed that phagocytic capacities of microglia were significantly ameliorated after EZH2 inhibition in co-culturing GBM cells and microglia proliferation was declined after addition of TGF?2 antibodies to co-incubated GBM cells with EZH2 inhibition. Besides, we found that EZH2 suppression in GBM cells enhanced co-culturing microglia engulfment through activation of iNOS.ConclusionsOur data demonstrates that EZH2 participates in GBM-induced immune deficient and EZH2 suppression in GBM can remodel microglia immune functions, which is beneficial for understanding GBM pathogenesis and suggests potential targets for therapeutic approaches.

Dataset Information

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

Publications

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

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