CD8型
癌症免疫疗法
生物
癌症研究
主要组织相容性复合体
免疫疗法
MHC I级
细胞毒性T细胞
T细胞
癌细胞
癌症
细胞生物学
免疫系统
免疫学
生物化学
遗传学
体外
作者
Yi Bao,Yuanyuan Qiao,Yuanyuan Qiao,Yuping Zhang,Rahul Mannan,Caleb Cheng,Tongchen He,Yang Zheng,Jiali Yu,Mahnoor Naseer Gondal,Gabriel Cruz,Sara Grove,Xuhong Cao,Fengyun Su,Rui Wang,Yu‐Sun Chang,Ilona Kryczek,Marcin Cieślik,Michael D. Green,Weiping Zou,Arul M. Chinnaiyan
标识
DOI:10.1073/pnas.2314416120
摘要
Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8 + T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8 + T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve -depletion were CD8 + T cell- and MHC-I-dependent, as CD8 + T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.
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