Glutamate-NMDAR receptors (GRINs) have been reported to influence cancer immunogenicity; however, the relationship between GRIN alterations and the response to immune checkpoint inhibitors (ICIs) has not been determined. This study combined clinical characteristics and mutational profiles from multiple cohorts to form a discovery cohort (n = 901). The aim of this study was to investigate the correlation between the mutation status of the GRIN gene and the response to ICI therapy. Additionally, an independent ICI-treated cohort from the Memorial Sloan Kettering Cancer Center (MSKCC, N = 1513) was used for validation. Furthermore, this study explored the associations between GRIN2A mutations and intrinsic and extrinsic immunity using multiomics analysis. In the discovery cohort, patients with GRIN2A-MUTs had improved clinical outcomes, as indicated by a higher objective response rate (ORR: 36.8% vs 25.8%, P = 0.020), durable clinical benefit (DCB: 55.2% vs 38.7%, P = 0.005), prolonged progression-free survival (PFS: HR = 0.65; 95% CI 0.49 to 0.87; P = 0.003), and increased overall survival (OS: HR = 0.67; 95% CI 0.50 to 0.89; P = 0.006). Similar results were observed in the validation cohort, in which GRIN2A-MUT patients exhibited a significant improvement in overall survival (HR = 0.66; 95% CI = 0.49 to 0.88; P = 0.005; adjusted P = 0.045). Moreover, patients with GRIN2A-MUTs exhibited an increase in tumor mutational burden, high expression of costimulatory molecules, increased activity of antigen-processing machinery, and infiltration of various immune cells. Additionally, gene sets associated with cell cycle regulation and the interferon response were enriched in GRIN2A-mutated tumors. In conclusion, GRIN2A mutation is a novel biomarker associated with a favorable response to ICIs in multiple cancers.

据报道，谷氨酸-NMDAR 受体 (GRIN) 会影响癌症免疫原性；然而，GRIN 改变与免疫检查点抑制剂 (ICIs) 反应之间的关系尚未确定。这项研究结合了多个队列的临床特征和突变谱，形成了一个发现队列 ( n  = 901)。本研究的目的是探讨 GRIN 基因突变状态与 ICI 治疗反应之间的相关性。 此外，还使用来自纪念斯隆凯特琳癌症中心 (MSKCC，N = 1513) 的独立 ICI 治疗队列进行验证。此外，本研究利用多组学分析探讨了 GRIN2A 突变与内在和外在免疫之间的关联。在发现队列中，GRIN2A-MUT 患者的临床结果有所改善，表现为更高的客观缓解率（ORR：36.8% vs 25.8%，P  = 0.020）、持久的临床获益（DCB：55.2% vs 38.7%，P）  = 0.005），延长无进展生存期（PFS：HR = 0.65；95% CI 0.49 至 0.87；P  = 0.003），并增加总生存期（OS：HR = 0.67；95% CI 0.50 至 0.89；P  = 0.006） 。在验证队列中也观察到了类似的结果，其中 GRIN2A-MUT 患者的总生存率显着改善（HR = 0.66；95% CI = 0.49 至 0.88；P  = 0.005；调整后的P  = 0.045）。此外，携带GRIN2A-MUT的患者表现出肿瘤突变负荷增加、共刺激分子高表达、抗原加工机制活性增加以及各种免疫细胞浸润。此外，与细胞周期调节和干扰素反应相关的基因集在 GRIN2A 突变肿瘤中丰富。总之，GRIN2A 突变是一种新型生物标志物，与多种癌症中 ICI 的良好反应相关。