PDF(Pubmed)
Abstract：
The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
摘要：
癌症治疗的现代医疗设备包括免疫治疗和靶向治疗，如蛋白激酶抑制剂。然而,癌症靶向药物有效动员树突状细胞(DCs)和影响免疫治疗的机制尚不清楚.这里,我们报告说，在临床相关蛋白激酶抑制剂的共有基因靶标中，在接受免疫检查点阻断(ICB)的患者中,PIKFYVE高表达对完全缓解的预测最少.在免疫细胞中，DC中PIKFYVE的高表达与ICB的不良反应相关。遗传和药理学研究表明，PIKfyve消融通过选择性改变替代/非经典NF-κB途径来增强DC功能。DC中Pikfyve的丢失和用阿吡莫德治疗，一种有效和特异性的PIKfyve抑制剂，抑制肿瘤生长，增强DC依赖性T细胞免疫，并增强了荷瘤小鼠模型中的ICB功效。此外，疫苗佐剂和阿吡莫德的组合在体内减少了肿瘤进展。因此，PIKfyve负控制DC，和PIKfyve抑制有望用于癌症免疫治疗和疫苗治疗策略。
