GRIN2A mutation is a novel indicator of stratifying beneficiaries of immune checkpoint inhibitors in multiple cancers

• Published in: Cancer gene therapy 2024-04, Vol.31 (4), p.586-598
• Main Authors: Li, Gan-xun, Chang, Rui-zhi, Liu, Tong-tong, Jin, Guan-nan, Lu, Kan, Yong, Tu-ying, Li, Zifu, Liu, Ji-hong, Zhang, Bixiang, Zhang, Wan-guang, Ding, Ze-yang
• Format: Article
• Language: English
• Subjects: 13/105; 13/95; 38/23; 38/39; 42/47; 631/67/68; 692/308/53; 692/53; 692/699/67/1857; 692/699/67/580; Antigen processing; Biomarkers; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Cell cycle; Clinical outcomes; Costimulator; Gene Expression; Gene Therapy; Glutamic acid receptors; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunogenicity; Immunotherapy; Interferons; Intervention; Medical prognosis; Metastases; Mutation; N-Methyl-D-aspartic acid receptors; Neoplasms - drug therapy; Neoplasms - genetics; Survival analysis
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/s41417-024-00730-6

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.