Blocking NHE1 stimulates glioma tumor immunity by restoring OXPHOS function of myeloid cells.
Blocking NHE1 stimulates glioma tumor immunity by restoring OXPHOS function of myeloid cells.
复制标题
阻断 NHE1 可通过恢复骨髓细胞的 OXPHOS 功能来刺激神经胶质瘤肿瘤免疫。
作者：
Hasan MN;Luo L;Ding D;Song S;Bhuiyan MIH;Liu R;Foley LM;Guan X;Kohanbash G;Hitchens TK;Castro MG;Zhang Z;Sun D
背景：胶质母细胞瘤（GBM）的免疫抑制肿瘤微环境（TME）是导致免疫治疗失败的因素之一。因此，迫切需要更好地了解TME，并确定新的TME调节剂，以实现更有效的GBM治疗。我们假设H+挤出蛋白Na/H交换器1 （NHE1）在GBM的糖代谢失调和免疫抑制中起作用。我们研究了阻断NHE1活性联合替莫唑胺（TMZ）治疗提高抗肿瘤免疫的效果。方法：采用小鼠同基因颅内胶质瘤模型，对DMSO（对照）、TMZ、NHE1特异性抑制剂HOE642、TMZ+HOE642 （T+H）联合4种治疗方案进行试验。体外1H/19氟磁共振成像（MRI）与细胞跟踪剂Vsense监测胶质瘤相关小胶质/髓样细胞（GAMs）的浸润情况。采用Seahorse分析仪和bulk rna测序分析糖代谢和转录组谱。在转基因Nhe1基因敲除（KO）小鼠中评估GAMs中选择性Nhe1缺失对抗pd -1治疗敏感性的影响。结果：在试验治疗方案中，T+H联合治疗显著刺激GAMs和T细胞的浸润；上调Th1激活和线粒体氧化磷酸化（OXPHOS）途径基因，增加葡萄糖摄取和线粒体质量，减少有氧糖酵解。Cx3cr1+ Nhe1 KO小鼠的Nhe1选择性缺失增加了抗肿瘤免疫和对TMZ +抗pd -1联合治疗的敏感性。结论：NHE1在神经胶质瘤免疫抑制性TME的发生中起一定作用，其部分机制是通过失调GAMs的糖代谢，并成为改善神经胶质瘤免疫的治疗靶点。
Background: Immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is one of the contributing factors for failed immunotherapies. Therefore, there is an urgent need to better understand TME and to identify novel modulators of TME for more effective GBM therapies. We hypothesized that H+ extrusion protein Na/H exchanger 1 (NHE1) plays a role in dysregulation of glucose metabolism and immunosuppression of GBM. We investigated the efficacy of blockade of NHE1 activity in combination with temozolomide (TMZ) therapy in increasing anti-tumor immunity. Methods: Mouse syngeneic intracranial glioma model was used to test four treatment regimens: DMSO (Vehicle-control), TMZ, NHE1 specific inhibitor HOE642, or TMZ+HOE642 (T+H) combination. Ex vivo 1H/19Fluorine magnetic resonance imaging (MRI) with cell tracking agent Vsense was performed to monitor the infiltration of glioma-associated microglia/myeloid cells (GAMs). Glucose metabolism and transcriptome profiles were analyzed by Seahorse analyzer and bulk RNA-sequencing. The impact of selective Nhe1 deletion in GAMs on sensitivity to anti-PD-1 therapy was evaluated in transgenic NHE1 knockout (KO) mice. Results: Among the tested treatment regimens, the T+H combination therapy significantly stimulated the infiltration of GAMs and T-cells; up-regulated Th1 activation, and mitochondrial oxidative phosphorylation (OXPHOS) pathway genes, increased glucose uptake and mitochondrial mass, and decreased aerobic glycolysis in GAMs. Selective deletion of Nhe1 in Cx3cr1+ Nhe1 KO mice increased anti-tumor immunity and sensitivity to TMZ plus anti-PD-1 combinatorial therapy. Conclusions: NHE1 plays a role in developing glioma immunosuppressive TME in part by dysregulating glucose metabolism of GAMs and emerges as a therapeutic target for improving glioma immunity.