Exploring the value of immune-related gene set score in gastric cancer prognosis and immunotherapy efficacy

Abstract

Aim: To characterize the gastric cancer immune landscape and evaluate its correlation with prognosis and immunotherapy efficacy.

Methods: Gene expression data from eight GEO datasets were preprocessed. The datasets were partitioned into training and validation subsets. Immune- and prognostic-related genes were identified from the training set to construct an Immune-Related Gene Set Score (IRGS) prediction model. The model underwent external validation in two independent cohorts, with further optimization incorporating clinical factors. Differences in immune biomarkers between IRGS groups were analyzed and their correlation with therapeutic response was assessed in an immune cohort.

Results: Elevated IRGS significantly correlated with prolonged overall survival (OS) in both training (HR 0.46, 0.37-0.56) and validation (HR 0.54, 0.39-0.74) sets (P < 0.001). External cohorts confirmed these findings (GSE84437 cohort, P = 0.002; GEO cohort, P = 0.003). IRGS correlated significantly with age, gender, and stage. Tumor microenvironment analysis showed positive associations between IRGS and key immunocyte populations, specifically B cells, CD4⁺ T cells, and M2 macrophages. Responders to immunotherapy had elevated IRGS scores than non-responders (P = 0.016).

Conclusions: The IRGS model is a robust predictor of prognosis and immunotherapy response in GC, underscoring its potential clinical utility.

Keywords

Gastric cancer / immune-related gene set score / prediction model / tumor microenvironment / immune checkpoint inhibitors

References

[1] Thrift AP,El-Serag HB.Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention.Nat Rev Clin Oncol2023;20:338-49

[2] Han B,Zeng H.Cancer incidence and mortality in China, 2022.J Natl Cancer Cent2024;4:47-53 PMCID:PMC11256708

[3] Kakeji Y,Suzuki S.A retrospective 5-year survival analysis of surgically resected gastric cancer cases from the Japanese Gastric Cancer Association nationwide registry (2001-2013).Gastric Cancer2022;25:1082-93

[4] Lan Q,Tian S.Mining TCGA database for genes of prognostic value in gastric cancer microenvironment.J Cell Mol Med2020;24:11120-32 PMCID:PMC7576220

[5] Quail DF.Microenvironmental regulation of tumor progression and metastasis.Nat Med2013;19:1423-37 PMCID:PMC3954707

[6] Xu L,Zhang S.Reshaping the systemic tumor immune environment (STIE) and tumor immune microenvironment (TIME) to enhance immunotherapy efficacy in solid tumors.J Hematol Oncol2022;15:87 PMCID:PMC9264569

[7] Li C,Peng E.Role of an exosomes-related lncRNAs signature in tumor immune microenvironment of gastric cancer.Front Cell Dev Biol2022;10:873319 PMCID:PMC9019506

[8] Sui X.Immune landscape and prognostic gene signatures in gastric cancer: implications for cachexia and clinical outcomes.Front Immunol2023;14:1297363 PMCID:PMC10682159

[9] Miliotis C,Katopodi XL.Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci.Nat Commun2024;15:4319 PMCID:PMC11109163

[10] Xu L,Liu Y.Unveiling KLHL23 as a key immune regulator in hepatocellular carcinoma through integrated analysis.Aging2024;16:13608-26 PMCID:PMC11723656

[11] Wu F,Tu Y.Sirtuin 7 super-enhancer drives epigenomic reprogramming in hepatocarcinogenesis.Cancer Lett2022;525:115-30

[12] Li B,Yang S.Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers.Mol Cancer2023;22:71 PMCID:PMC10111719

[13] Janjigian YY,Yañez P.The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer.Nature2021;600:727-30

[14] Janjigian YY,Bai Y.Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial.Lancet2023;402:2197-208

[15] Rha SY,Yañez P.Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial.Lancet Oncol2023;24:1181-95

[16] Janjigian YY,Moehler M.First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.Lancet2021;398:27-40 PMCID:PMC8436782

[17] Chao J,Shitara K.Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials.JAMA Oncol2021;7:895-902 PMCID:PMC8017478

[18] Galassi C,Vitale I.The hallmarks of cancer immune evasion.Cancer Cell2024;42:1825-63

[19] Germanà E,Pizzimenti C.Programmed cell death ligand 1 (PD-L1) immunohistochemical expression in advanced urothelial bladder carcinoma: an updated review with clinical and pathological implications.Int J Mol Sci2024;25:6750

[20] Russo AE.Gastric cancer etiology and management in Asia and the West.Annu Rev Med2019;70:353-67

[21] Peña-Romero AC.Dual effect of immune cells within tumour microenvironment: pro- and anti-tumour effects and their triggers.Cancers2022;14:1681 PMCID:PMC8996887

[22] Duan S,Liu F.Novel immune-risk score of gastric cancer: a molecular prediction model combining the value of immune-risk status and chemosensitivity.Cancer Med2019;8:2675-85 PMCID:PMC6537086

[23] Sun P,Li Z.Assessment of prognostic prediction models for gastric cancer using genomic and transcriptomic profiles.Meta Gene2021;28:100890

[24] Qiu L,He J.Predictive model for risk of gastric cancer using genetic variants from genome-wide association studies and high-evidence meta-analysis.Cancer Med2020;9:7310-6 PMCID:PMC7541133

[25] Cheong JH,Park S.Development and validation of a prognostic and predictive 32-gene signature for gastric cancer.Nat Commun2022;13:774 PMCID:PMC8828873

[26] Xu X,Wu Y.A signature of seven immune-related genes predicts overall survival in male gastric cancer patients.Cancer Cell Int2021;21:117

[27] Jiang B,Tong Y.An immune-related gene signature predicts prognosis of gastric cancer.Medicine2019;98:e16273

[28] Li C,Yi X,Okita R.Pan-cancer prognostic model and immune microenvironment analysis of natural killer cell-related genes.Transl Cancer Res2024;13:1936-53

[29] Liu Y,Chen Y.Integrated bioinformatics analysis for conducting a prognostic model and identifying immunotherapeutic targets in gastric cancer.BMC Bioinformatics2023;24:191 PMCID:PMC10170748

[30] Molinaro C,Cailliau K.Proteins from the DNA damage response: regulation, dysfunction, and anticancer strategies.Cancers2021;13:3819 PMCID:PMC8345162

[31] Wang M,Ao D.Targeting DNA repair pathway in cancer: mechanisms and clinical application.MedComm2021;2:654-91

[32] Chen M,van Vugt MATM.Genomic instability, inflammatory signaling and response to cancer immunotherapy.Biochim Biophys Acta Rev Cancer2022;1877:188661

[33] Shi C,Lin A.The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy.J Exp Clin Cancer Res2022;41:268 PMCID:PMC9450390

[34] Ye Z,Lees-Miller SP.Function and molecular mechanism of the DNA damage response in immunity and cancer immunotherapy.Front Immunol2021;12:797880 PMCID:PMC8712645

[35] Zhou C,Cao M.Activation of the DDR pathway leads to the down-regulation of the TGFβ pathway and a better response to ICIs in patients with metastatic urothelial carcinoma.Front Immunol2021;12:634741

[36] Lou S,Zhang J.Patient-level DNA damage repair pathway profiles and anti-tumor immunity for gastric cancer.Front Immunol2021;12:806324

[37] Graves EE,Le QT.The tumor microenvironment in non-small-cell lung cancer.Semin Radiat Oncol2010;20:156-63 PMCID:PMC2917385

[38] Roma-Rodrigues C,Baptista PV.Targeting tumor microenvironment for cancer therapy.Int J Mol Sci2019;20:840 PMCID:PMC6413095

[39] Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth.Cancer Cell2023;41:374-403

[40] Sun Y,Fu Y.Metabolic reprogramming involves in transition of activated/resting CD4⁺ memory T cells and prognosis of gastric cancer.Front Immunol2023;14:1275461

[41] Wang F,Yu J.The role of natural killer cell in gastrointestinal cancer: killer or helper.Oncogene2021;40:717-30

[42] Li J,Zeng Z.Tumour-associated macrophages in gastric cancer: from function and mechanism to application.Clin Transl Med2023;13:e1386 PMCID:PMC10444973

[43] Sukri A,Kosai NR.The roles of immune cells in gastric cancer: anti-cancer or pro-cancer?.Cancers2022;14:3922

[44] Cai X,Guo Y,Zheng C.Re-analysis of single cell and spatial transcriptomics data reveals B cell landscape in gastric cancer microenvironment and its potential crosstalk with tumor cells for clinical prognosis.J Transl Med2024;22:807