Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity.
Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity.
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克霉唑调节树突状细胞乳酸溶酶体轴增强抗肿瘤免疫力
DOI：
10.1136/jitc-2020-002155
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发表时间：
2021-05
影响因子：
10.9
通讯作者：
Xia X
中科院分区：
文献类型：
--
作者：
Wang Z;Xu F;Hu J;Zhang H;Cui L;Lu W;He W;Wang X;Li M;Zhang H;Xiong W;Xie C;Liu Y;Zhou P;Liu J;Huang P;Qin XF;Xia X
树突状细胞（DC）在抗肿瘤免疫中起着关键作用，但DC介导的肿瘤疫苗的治疗效果仍然很低，部分原因是DC在肿瘤抗原呈递中的功能不稳定。因此，鉴定能够增强基于DC的抗肿瘤免疫的药物并揭示其潜在机制可能为癌症免疫治疗提供新的治疗选择。采用体外抗原提呈试验筛选DC调节药物。通过流式细胞术、ELISA或qPCR测量DC和T细胞的功能。使用B16、MC 38、CT 26肿瘤模型和C57 BL/6、Balb/c、裸鼠和Batf 3 −/−小鼠分析克霉唑治疗的体内治疗效果和对肿瘤免疫微环境的影响。通过筛选一组小分子抑制剂和美国食品药品监督管理局（FDA）批准的药物，我们确定了克霉唑，一种抗真菌药物，可以促进DC介导的抗原提呈和增强T细胞反应。克霉唑作用于己糖激酶2调节乳酸代谢产生，增强DCs中溶酶体途径和Chop表达，随后诱导DC成熟和T细胞活化。重要的是，克霉唑体内给药诱导肿瘤内免疫浸润，抑制依赖于DC和CD 8 + T细胞的肿瘤生长，并增强抗PD 1抗体的抗肿瘤功效。我们的研究结果表明，克霉唑可以通过乳酸-溶酶体轴触发DC激活，以促进抗原交叉呈递，并可用作潜在的联合治疗方法，以提高抗PD 1免疫治疗的治疗效果。
Dendritic cells (DCs) play a critical role in antitumor immunity, but the therapeutic efficacy of DC-mediated cancer vaccine remains low, partly due to unsustainable DC function in tumor antigen presentation. Thus, identifying drugs that could enhance DC-based antitumor immunity and uncovering the underlying mechanism may provide new therapeutic options for cancer immunotherapy. In vitro antigen presentation assay was used for DC-modulating drug screening. The function of DC and T cells was measured by flow cytometry, ELISA, or qPCR. B16, MC38, CT26 tumor models and C57BL/6, Balb/c, nude, and Batf3−/− mice were used to analyze the in vivo therapy efficacy and impact on tumor immune microenvironment by clotrimazole treatment. By screening a group of small molecule inhibitors and the US Food and Drug Administration (FDA)-approved drugs, we identified that clotrimazole, an antifungal drug, could promote DC-mediated antigen presentation and enhance T cell response. Mechanistically, clotrimazole acted on hexokinase 2 to regulate lactate metabolic production and enhanced the lysosome pathway and Chop expression in DCs subsequently induced DC maturation and T cell activation. Importantly, in vivo clotrimazole administration induced intratumor immune infiltration and inhibited tumor growth depending on both DCs and CD8+ T cells and potentiated the antitumor efficacy of anti-PD1 antibody. Our findings showed that clotrimazole could trigger DC activation via the lactate-lysosome axis to promote antigen cross-presentation and could be used as a potential combination therapy approach to improving the therapeutic efficacy of anti-PD1 immunotherapy.
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DOI：
10.4049/jimmunol.1302498
发表时间：
2014-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
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2008-03-01
期刊：
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影响因子：
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通讯作者：
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作者：
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通讯作者：
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DOI：
10.1084/jem.20151570
发表时间：
2016-01-11
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.1011736107
发表时间：
2010-10-12
影响因子：
11.1
作者：
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通讯作者：
Gaston, J. S. Hill