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

Cancer Gene Therapy volume 31, pages 586–598 (2024)Cite this article

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Abstract

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.

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Fig. 1: Flowchart of the process used for screening the population in this study.
Fig. 2: Association between GRIN2A mutation and clinical outcomes in the discovery cohort.
Fig. 3: Validation of the predictive value of mutated GRIN2A.
Fig. 4: Frequencies and enrichment of biological processes associated with mutated GRIN2A in the TCGA cohort.
Fig. 5: Intrinsic immune response mechanisms associated with GRIN2A mutation.
Fig. 6: Extrinsic immune response mechanisms associated with GRIN2A mutation.
Fig. 7: Graphical illustration of this study.

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Data availability

The clinicopathological data of patients in the cohorts or patients treated with immune checkpoint agents are described in the Materials and Methods and Supporting Data. The resources, tools and codes used in our analyses are described in the “Methods” section. Other data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank Drs. Xundong Zhang, and Xing-jie Hao (School of Public Health, Tongji Medical College, HUST) for their support in the bioinformatics analyses of this study.

Funding

This work was supported by the National Nature Science Foundation of China (No. 82273441 and 81874065), the National Basic Research Program of China (2020YFA0710700), the Knowledge Innovation Program of Wuhan-Shuguang Project (No. 2022020801020456), the Tongji Hospital (HUST) Foundation for Excellent Young Scientist (No. 2020YQ05), and the first level of the Public Health Youth Top Talent Project of Hubei Province (No. 2022SCZ051).

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Author notes

  1. These authors contributed equally: Gan-xun Li, Rui-zhi Chang, Tong-tong Liu, Guan-nan Jin.

Authors and Affiliations

  1. Hepatic Surgery Center, and Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Gan-xun Li, Rui-zhi Chang, Kan Lu, Bixiang Zhang, Wan-guang Zhang & Ze-yang Ding

  2. Department of Anesthesiology, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Tong-tong Liu

  3. Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China

    Guan-nan Jin

  4. National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430071, Hubei, China

    Tu-ying Yong & Zifu Li

  5. Department and Institute of Urology, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Ji-hong Liu

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Contributions

Study concept and design: ZD, WZ, and BZ. Acquisition, analysis, interpretation of the data, critical revision of the manuscript: all the authors. Drafting of the manuscript: GL, TL, GJ and ZD. Study supervision: BZ and WZ.

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Correspondence to Bixiang Zhang, Wan-guang Zhang or Ze-yang Ding.

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Competing interests

ZD served as a speaker and consultant for Bayer, Eisai, Roche, MSD, Astra-Zeneca, Innovent, Hengrui, and BeiGene. The remaining authors have nothing to disclose.

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All the data used in this study are deidentified and publicly available. Therefore, the Institutional Review Board (IRB) of Tongji Hospital was waived.

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Li, Gx., Chang, Rz., Liu, Tt. et al. GRIN2A mutation is a novel indicator of stratifying beneficiaries of immune checkpoint inhibitors in multiple cancers. Cancer Gene Ther 31, 586–598 (2024). https://doi.org/10.1038/s41417-024-00730-6

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