Abstract
The weak immunogenicity of gliomas presents a barrier for effective immunotherapy. Na/H exchanger isoform 1 (NHE1) maintains alkaline intracellular pH (pHi) 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.
Highlights
Patients with glioblastoma (GBM), World HealthOrganization grade IV tumor, presently persist short median post-diagnosis survival time, despite of surgical resection followed by radiotherapy and temozolomide (TMZ)-mediated chemotherapy[1,2,3]
Elevated Na/H exchanger isoform 1 (NHE1) mRNA expression in human glioma tissues To better understand the role of NHE1 in the progression of glioma, we compared the overall survival time of glioma patients between the group with high and low NHE1 (SLC9A1) mRNA expression in the GSE16011 cohort
Kaplan–Meier survival curve showed that the patients with high level of NHE1 mRNA in glioma tissues had a shorter overall survive (p < 0.001, Fig. 1a)
Summary
Organization grade IV tumor, presently persist short median post-diagnosis survival time (approximately 20 months), despite of surgical resection followed by radiotherapy and temozolomide (TMZ)-mediated chemotherapy[1,2,3]. The obstacles in glioma therapy damage via the function of DNA repair protein. O6-methylguanine-DNA methyltransferase (MGMT), incomplete surgical resection due to the highly aggressive behavior of glioma and glioma stem cells, and tumorsupportive microenvironment[4,5,6]. Developed cancer immunotherapy provides promising survival benefits in some patients[7], but other patients are not responsive to the therapy[8,9,10,11] and tumor relapse is common[12,13]. Successful antitumor immunotherapy depends on an immunogenic tumor microenvironment and the interactions between cancer cells and enhanced T cell antitumor immunity[14]. A non-immunogenic, immunosuppressive tumor microenvironment may lead to exiguous clinical benefit[15]
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