机构：[1]Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.重点科室诊疗科室神经外科神经外科首都医科大学附属天坛医院[2]Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.[3]Chinese National Clinical Research Center for Neurological Diseases, Beijing, China.[4]Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.[5]Department of Neurology, University of California, San Francisco, CA, USA.[6]Department of Neurological Surgery, University of California, San Francisco, CA, USA.[7]Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.[8]Beijing Neurosurgical Institute, Beijing, China研究所北京市神经外科研究所首都医科大学附属天坛医院
The weak immunogenicity of gliomas presents a barrier for effective immunotherapy. Na/H exchanger isoform 1 (NHE1) maintains alkaline intracellular pH (pH(i)) of glioma cells and acidic microenvironment. In addition, NHE1 is expressed in tumor-associated microglia and tumor-associated macrophages (TAMs) and involved in protumoral communications between glioma and TAMs. Therefore, we hypothesize that NHE1 plays a role in developing tumor resistance and immunosuppressive tumor microenvironment. In this study, we investigated the efficacy of pharmacological inhibition of NHE1 on combinatorial therapies. Here we show that temozolomide (TMZ) treatment stimulates NHE1 protein expression in two intracranial syngeneic mouse glioma models (SB28, GL26). Pharmacological inhibition of NHE1 potentiated the cytotoxic effects of TMZ, leading to reduced tumor growth and increased median survival of mice. Blockade of NHE1 stimulated proinflammatory activation of TAM and increased cytotoxic T cell infiltration into tumors. Combining TMZ, anti-PD-1 antibody treatment with NHE1 blockade significantly prolonged the median survival in the mouse glioma model. These results demonstrate that pharmacological inhibition of NHE1 protein presents a new strategy for potentiating TMZ-induced cytotoxicity and increasing tumor immunogenicity for immunotherapy to improve glioma therapy.
基金：
NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01NS75995]
第一作者机构：[1]Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.[2]Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.[3]Chinese National Clinical Research Center for Neurological Diseases, Beijing, China.
通讯作者：
通讯机构：[1]Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.[2]Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.[3]Chinese National Clinical Research Center for Neurological Diseases, Beijing, China.[8]Beijing Neurosurgical Institute, Beijing, China
推荐引用方式(GB/T 7714)：
Guan Xiudong,Hasan Md Nabiul,Begum Gulnaz,et al.Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy[J].CELL DEATH & DISEASE.2018,9(10):-.doi:10.1038/s41419-018-1062-3.
APA：
Guan, Xiudong,Hasan, Md Nabiul,Begum, Gulnaz,Kohanbash, Gary,Carney, Karen E....&Sun, Dandan.(2018).Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy.CELL DEATH & DISEASE,9,(10)
MLA：
Guan, Xiudong,et al."Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy".CELL DEATH & DISEASE 9..10(2018):-
生物学