抗真菌药物克霉唑调控抗肿瘤免疫的功能和机制研究

肿瘤免疫疗法在多种肿瘤的治疗上取得巨大进展，而治疗性肿瘤疫苗作为免疫疗法的一个重要分支，目前在临床上疗效欠佳，其主要原因是未能完全激活体内的树突状细胞。我们的前期研究表明，一种常用的抗真菌药克霉唑具有抗肿瘤功效，并且其体内抗肿瘤效应需要免疫系统特别是CD8 T细胞的介导。进一步研究发现克霉唑在体外通过激活树突状细胞来活化抗原特异性T细胞反应杀伤肿瘤。转录组测序分析发现克霉唑能够增强树突状细胞中的溶酶体相关的信号通路，提示克霉唑通过影响溶酶体功能来激活树突状细胞的抗原提呈功能，并且可以作为抗原佐剂提高肿瘤疫苗的抗肿瘤效果。本项目将进一步明确克霉唑在体内激活树突状细胞抗肿瘤的效应，并阐明克霉唑激活树突状细胞的分子机制；最后在体内验证克霉唑作为抗原佐剂对肿瘤疫苗治疗肿瘤疗效的影响。本项目的完成有望揭示克霉唑强化抗肿瘤免疫的分子机制，为设计新型肿瘤疫苗和组合免疫疗法治疗肿瘤提供前期理论和实验依据。

Cancer immunotherapy has revolutionized the therapeutic landscape in treating multiple types of cancers. However, the response rate and anti-tumor efficacy was still limited, especially for cancer vaccine. How to expand the applicable population and improve the therapy efficacy is a critical problem for cancer immunotherapy. Recent reports found that a commonly used antifungal drug, clotrimazole, exhibited antitumor function on some tumor animal models，but its impact on antitumor immunity is unknown. Our preliminary findings showed that antitumor efficacy of clotrimazole requires host adaptive immunity, especially CD8 T cells. Clotrimazole doesn't activate T cells directly, but induces antigen-specific T cells through antigen-specific T cell responses. Transcriptome analysis identified lysosome/lytic vacoule as a major pathway affected by clotrimazole. Thus, we hypothesize that clotrimazole may potentiate antigen presentation function of dendritic cells through regulating lysosome pathway, and boost antitumor efficacy of cancer vaccine as a vaccine adjuvant. To test this hypothesis, we plan to 1. determine the in vivo effect of clotrimazole on antitumor function of dendritic cells; 2. define the molecular and cellular mechanisms by which clotrimazole activate dendritic cells; 3. evaluate the antitumor efficacy of cancer vaccine using clotrimazole as a vaccine adjuvant. Our research may identify new molecular and cellular mechanism by which clotrimazole exhibit its antitumor function, and provide preclinical evidence for developing new therapeutic means to improve antitumor efficacy of cancer vaccine.