Tumor microenvironment evaluation promotes precise checkpoint immunotherapy of advanced gastric cancer

作者：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^*

来源：Journal for ImmunoTherapy of Cancer, 2021, 9(8): e002467.

DOI：10.1136/jitc-2021-002467

• tumor microenvironment
• computational biology
• gastrointestinal neoplasms
• immunotherapy

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.

• 单位
  中山大学; i; 广州中医药大学; 南方医科大学; 6; 1; 广东省人民医院