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Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity

克霉唑 抗原呈递 免疫系统 树突状细胞 医学 癌症研究 免疫疗法 抗原 癌症免疫疗法 体内 药理学 免疫学 离体 肿瘤抗原 溶酶体 肿瘤微环境 T细胞 生物 生物化学 抗真菌 生物技术 皮肤病科
作者
Zining Wang,Feifei Xu,Jie Hu,Hongxia Zhang,Lei Cui,Wenhua Lu,Wenzhuo He,Xiaojuan Wang,Mengyun Li,Huanling Zhang,Wenjing Xiong,C. Xie,Yongxiang Liu,Penghui Zhou,Jinyun Liu,Peng Huang,Xiaofeng Qin,Xiaojun Xia
出处
期刊:Journal for ImmunoTherapy of Cancer [BMJ]
卷期号:9 (5): e002155-e002155 被引量:17
标识
DOI:10.1136/jitc-2020-002155
摘要

Background 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. Methods 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. Results 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. Conclusions 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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