Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity.
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.
['Wang|Zining|Z|', 'Xu|Feifei|F|', 'Hu|Jie|J|', 'Zhang|Hongxia|H|', 'Cui|Lei|L|', 'Lu|Wenhua|W|', 'He|Wenzhuo|W|', 'Wang|Xiaojuan|X|', 'Li|Mengyun|M|', 'Zhang|Huanling|H|', 'Xiong|Wenjing|W|', 'Xie|Chunyuan|C|', 'Liu|Yongxiang|Y|', 'Zhou|Penghui|P|', 'Liu|Jinyun|J|', 'Huang|Peng|P|', 'Qin|Xiaofeng Frank|XF|', 'Xia|Xiaojun|X|0000-0003-4444-7472']
dendritic cells immunotherapy