PT - JOURNAL ARTICLE AU - Wang, Zining AU - Xu, Feifei AU - Hu, Jie AU - Zhang, Hongxia AU - Cui, Lei AU - Lu, Wenhua AU - He, Wenzhuo AU - Wang, Xiaojuan AU - Li, Mengyun AU - Zhang, Huanling AU - Xiong, Wenjing AU - Xie, Chunyuan AU - Liu, Yongxiang AU - Zhou, Penghui AU - Liu, Jinyun AU - Huang, Peng AU - Qin, Xiaofeng Frank AU - Xia, Xiaojun TI - Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity AID - 10.1136/jitc-2020-002155 DP - 2021 May 01 TA - Journal for ImmunoTherapy of Cancer PG - e002155 VI - 9 IP - 5 4099 - http://jitc.bmj.com/content/9/5/e002155.short 4100 - http://jitc.bmj.com/content/9/5/e002155.full SO - J Immunother Cancer2021 May 01; 9 AB - 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.Data are available upon reasonable request.