Tumor microenvironment evaluation promotes precise checkpoint immunotherapy of advanced gastric cancer

• Published in: Journal for immunotherapy of cancer Vol. 9; no. 8; p. e002467
• Main Authors: Zeng, Dongqiang, Wu, Jiani, Luo, Huiyan, Li, Yong, Xiao, Jian, Peng, Jianjun, Ye, Zilan, Zhou, Rui, Yu, Yunfang, Wang, Gaofeng, Huang, Na, Wu, Jianhua, Rong, Xiaoxiang, Sun, Li, Sun, Huiying, Qiu, Wenjun, Xue, Yichen, Bin, Jianping, Liao, Yulin, Li, Nailin, Shi, Min, Kim, Kyoung-Mee, Liao, Wangjun
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.08.2021; BMJ Publishing Group
• Series: Original research
• Subjects: Adult; Aged; Algorithms; Apoptosis; Biomarkers; Cancer; Cancer research; Clinical trials; Computational Biology - methods; Female; Gastric cancer; Gene expression; Generalized linear models; Genomes; Hospitals; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Immunotherapy - methods; Immunotherapy Biomarkers; Male; Medicin och hälsovetenskap; Melanoma; Metabolism; Metastasis; Middle Aged; Mutation; Patients; Prospective Studies; Proteins; Stomach Neoplasms - drug therapy; Tumor Microenvironment; computational biology; gastrointestinal neoplasms; tumor microenvironment; immunotherapy
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-002467

BackgroundDurable efficacy of immune checkpoint blockade (ICB) occurred in a small number of patients with metastatic gastric cancer (mGC) and the determinant biomarker of response to ICB remains unclear.MethodsWe developed an open-source TMEscore R package, to quantify the tumor microenvironment (TME) to aid in addressing this dilemma. Two advanced gastric cancer cohorts (RNAseq, N=45 and NanoString, N=48) and other advanced cancer (N=534) treated with ICB were leveraged to investigate the predictive value of TMEscore. Simultaneously, multi-omics data from The Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD) and Asian Cancer Research Group (ACRG) were interrogated for underlying mechanisms.ResultsThe predictive capacity of TMEscore was corroborated in patient with mGC cohorts treated with pembrolizumab in a prospective phase 2 clinical trial (NCT02589496, N=45, area under the curve (AUC)=0.891). Notably, TMEscore, which has a larger AUC than programmed death-ligand 1 combined positive score, tumor mutation burden, microsatellite instability, and Epstein-Barr virus, was also validated in the multicenter advanced gastric cancer cohort using NanoString technology (N=48, AUC=0.877). Exploration of the intrinsic mechanisms of TMEscore with TCGA and ACRG multi-omics data identified TME pertinent mechanisms including mutations, metabolism pathways, and epigenetic features.ConclusionsCurrent study highlighted the promising predictive value of TMEscore for patients with mGC. Exploration of TME in multi-omics gastric cancer data may provide the impetus for precision immunotherapy.