GRIN2A Mutations as a Novel Indicator for Stratifying Beneficiaries of Immune Checkpoint Inhibitors in Various Cancers

Background

Immune checkpoint inhibitors (ICIs) therapy, which modulates the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death (ligand) 1 (PD-(L)1) pathways, has made revolutionary progress in treating various cancers. Despite the significant efficacy of ICIs, the clinical response varies greatly among different tumor patients. Therefore, identifying reliable biomarkers to predict ICI response is urgently needed to develop more precise therapeutic interventions. Several biomarkers have been associated with ICI responses, including immune checkpoint levels, tumor mutation burden (TMB), aneuploidy scores, insertion-deletion variations, single nucleotide variant (SNV) neoantigen burden, microsatellite instability, lymphocyte infiltration, specific gene mutations, and copy number variations (CNA). However, these biomarkers still have limitations in practical applications.

N-methyl-D-aspartate receptors (NMDAR) are heterotetrameric complexes composed of two NR1 (GRIN1) and two NR2 (GRIN2(A–D)) subunits, mainly overexpressed in neural cells. NMDAR, through binding with ligands such as glutamate, promotes the influx of calcium ions (Ca²⁺), thereby activating calcium-dependent signaling pathways. These receptors play crucial roles in various neurobiological processes and disease pathologies, including learning, memory, neurodegenerative diseases, epilepsy, and tumorigenesis, and significantly impact tumor immunity. Recent clinical trials have shown improved prognosis in patients receiving anti-angiogenic and ICI treatments, suggesting that NMDAR, as a potential angiogenic tumor endothelial biomarker, may influence the efficacy of immunotherapy. Thus, NMDAR gene mutations may play an important role in predicting the response to immunotherapy. However, the association between NMDAR genomic alterations and ICI response has not been thoroughly studied.

Study Source

This study was conducted by a team from Tongji Medical College, Huazhong University of Science and Technology, including Ganxun Li, Ruizhi Chang, Tongtong Liu, Guannan Jin, Kan Lu, Tuxing Yong, Zifu Li, and Jihong Liu, and published in the journal Cancer Gene Therapy in 2024. These authors are from various departments at Tongji Hospital of Huazhong University of Science and Technology, including the Liver Surgery Center, Anesthesiology, Nephrology, National Engineering Research Center, and Urology.

Research Methodology

The study consisted of three main parts: discovery cohort, validation cohort, and non-ICI treatment cohort analysis.

Discovery Cohort

First, the study systematically collected whole-exome sequencing (WES) data and corresponding clinical annotations from 901 patients treated with ICIs. These patients came from six previously published studies and included five cancer types: non-small cell lung cancer (NSCLC), melanoma, head and neck squamous cell carcinoma (HNSCC), renal clear cell carcinoma (RCC), and bladder cancer. Standard quality control and mutation calling pipelines were used to process all raw data, excluding samples with low sequencing coverage or low tumor purity. The GRIN2A mutations in the NR2 subunit were selected as the primary study focus.

Validation Cohort

The validation cohort included 1513 patients with various cancer types from Memorial Sloan Kettering Cancer Center (MSKCC). These patients also received ICI treatment, and their genomic data and clinical outcomes were analyzed to confirm the results of the discovery cohort.

Non-ICI Treatment Cohort

To further explore the prognostic impact of GRIN2A mutations in patients not treated with ICIs, the study included relevant patients from four sources. These data sources included studies by Samstein et al., TCGA, ICGC, and CPTAC projects.

Experimental Results

Results of the Discovery Cohort

In the discovery cohort, patients with GRIN2A mutations exhibited higher objective response rates (ORR: 36.8% vs 25.8%) and durable clinical benefits (DCB: 55.2% vs 38.7%), along with significantly longer progression-free survival (PFS) and overall survival (OS).

Results of the Validation Cohort

The results of the validation cohort were consistent with the discovery cohort, showing significant overall survival improvements in patients with GRIN2A mutations. Moreover, even after adjusting for potential confounding factors (such as gender, age, medication, tumor purity, CNA, and TMB levels), patients with GRIN2A mutations still had significantly longer survival.

Results of the Non-ICI Treatment Cohort

However, in four independent non-ICI treatment cohorts, there was no significant difference in prognosis between patients with and without GRIN2A mutations.

Conclusion and Research Significance

The study indicates that GRIN2A mutations are associated with favorable prognosis in patients receiving ICI treatment for various cancers. Biologically, patients with GRIN2A mutations display higher tumor immunogenicity and more anti-tumor immune cell infiltration, potentially explaining their better treatment response.

This study systematically analyzes the relationship between NMDAR gene mutations and clinical outcomes in cancer patients receiving ICI treatment for the first time. It not only identifies GRIN2A mutations as a new therapeutic biomarker but also deeply explores its role in the tumor immune environment, providing valuable theoretical support for subsequent clinical research and therapeutic strategies.

Study Highlights

1. Newly Discovered Biomarker: GRIN2A mutations as a novel biomarker indicating the effectiveness of immunotherapy.
2. Multidimensional Validation: Highly reliable results validated through multidimensional data analysis from the discovery and validation cohorts.
3. In-depth Mechanistic Exploration: Multi-omic analysis revealing possible mechanisms of GRIN2A mutations in immune response.

Additional Information

The authors suggest the need for larger scale prospective clinical trials to validate the efficacy of GRIN2A mutations as predictive biomarkers. Furthermore, the study emphasizes the importance of further experimental exploration of the molecular mechanisms linking GRIN2A mutations and immune therapy response.

This research provides a new perspective and direction for cancer immunotherapy, promoting the development of personalized treatment and holding significant scientific and clinical application value.