Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype.
Degao ChenJing XieRoland FiskesundWenqian DongXiaoyu LiangJiadi LvXun JinJinyan LiuSiqi MoTianzhen ZhangFeiran ChengYabo ZhouHuafeng ZhangKe TangJingwei MaYuying LiuBo HuangPublished in: Nature communications (2018)
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.
Keyphrases
- immune response
- induced apoptosis
- transcription factor
- cell cycle arrest
- protein kinase
- adipose tissue
- stem cells
- oxidative stress
- emergency department
- dendritic cells
- big data
- cell death
- cell proliferation
- machine learning
- toll like receptor
- deep learning
- climate change
- risk assessment
- artificial intelligence
- dna binding