RT Journal Article
SR Electronic
T1 Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e002155
DO 10.1136/jitc-2020-002155
VO 9
IS 5
A1 Wang, Zining
A1 Xu, Feifei
A1 Hu, Jie
A1 Zhang, Hongxia
A1 Cui, Lei
A1 Lu, Wenhua
A1 He, Wenzhuo
A1 Wang, Xiaojuan
A1 Li, Mengyun
A1 Zhang, Huanling
A1 Xiong, Wenjing
A1 Xie, Chunyuan
A1 Liu, Yongxiang
A1 Zhou, Penghui
A1 Liu, Jinyun
A1 Huang, Peng
A1 Qin, Xiaofeng Frank
A1 Xia, Xiaojun
YR 2021
UL http://jitc.bmj.com/content/9/5/e002155.abstract
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.