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

Degao Chen,Wenqian Dong,Jiadi Lv,Yabo Zhou,Ke Tang,Feiran Cheng,Bo Huang,Jing Xie,Tianzhen Zhang,Xun Jin,Jinyan Liu,Huafeng Zhang,Roland Fiskesund,Yuying Liu,Xiaoyu Liang,Siqi Mo,Jingwei Ma

doi:10.1038/s41467-018-03225-9

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.

Highlights

Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity
We focused on mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signal molecules, because (1) MAPK and NF-κB are activated in IFN-γ/ LPS-induced M1 macrophages[8,10,29,30,31]; (2) MAPK and NF-κB are the key regulator of proinflammatory factors[32]; and (3) proinflammatory factors are upregulated in the above settings
CQ’s antitumor effect disappears in macrophage-deficient mice, suggesting that CQ uses macrophages as a means to activate antitumor T-cell immune response. In support of this notion, we found that macrophages in tumor microenvironment are reset by CQ from tumor-promoting M2 to tumor-inhibiting M1 phenotype

Summary

Introduction

Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality. Targeting TAMs is considered as a promising strategy in cancer immunotherapy[3,4,5] Notwithstanding their tumorpromoting effects, macrophages are capable of killing tumor cells by releasing nitrogen oxide (NO) and interferon-γ (IFN-γ)[6,7]. We provide evidence that CQ functions as an immune modulator and mediates its antitumor efficacy via resetting TAMs from M2 to M1 phenotype

Methods

Results

Conclusion