Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype.
Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype.
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氯喹通过将肿瘤相关巨噬细胞重置为 M1 表型来调节抗肿瘤免疫反应
DOI：
10.1038/s41467-018-03225-9
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发表时间：
2018-02-28
影响因子：
16.6
通讯作者：
Huang B
中科院分区：
文献类型：
--
作者：
Chen D;Xie J;Fiskesund R;Dong W;Liang X;Lv J;Jin X;Liu J;Mo S;Zhang T;Cheng F;Zhou Y;Zhang H;Tang K;Ma J;Liu Y;Huang B
重置肿瘤相关巨噬细胞（TAMs）是改善免疫抑制性肿瘤微环境，提高先天性和适应性抗肿瘤免疫的一种有前途的策略。在这里，我们表明，氯喹（CQ），一种经过验证的抗疟疾药物，可以作为一种抗肿瘤免疫调节剂，开关TAM从M2到肿瘤杀伤M1表型。从机制上讲，CQ增加巨噬细胞溶酶体pH值，通过溶酶体Ca 2+通道粘磷脂-1（Mcoln 1）引起Ca 2+释放，从而诱导p38和NF-κB活化，从而使TAM极化为M1表型。同时，释放的Ca 2+激活转录因子EB（TFEB），其将TAM的代谢从氧化磷酸化重新编程为糖酵解。因此，CQ重置巨噬细胞通过减少髓源性抑制细胞和Treg细胞的免疫抑制性浸润来改善肿瘤免疫微环境，从而增强抗肿瘤T细胞免疫。这些数据阐明了CQ以前未被认识的抗肿瘤机制，表明了一种潜在的新的基于巨噬细胞的肿瘤免疫模式。
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.
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影响因子：
8.8
作者：
Holmgaard RB;Zamarin D;Li Y;Gasmi B;Munn DH;Allison JP;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
30.5
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64.8
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De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
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Merghoub T
影响因子：
50.3
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Kumar V;Donthireddy L;Marvel D;Condamine T;Wang F;Lavilla-Alonso S;Hashimoto A;Vonteddu P;Behera R;Goins MA;Mulligan C;Nam B;Hockstein N;Denstman F;Shakamuri S;Speicher DW;Weeraratna AT;Chao T;Vonderheide RH;Languino LR;Ordentlich P;Liu Q;Xu X;Lo A;Puré E;Zhang C;Loboda A;Sepulveda MA;Snyder LA;Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
3.3
作者：
Canton J;Khezri R;Glogauer M;Grinstein S
通讯作者：
Grinstein S