Tumor microenvironment evaluation promotes precise checkpoint immunotherapy of advanced gastric cancer.

Abstract

BACKGROUND:

Durable 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.

METHODS:

We 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.

RESULTS:

The 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.

CONCLUSIONS:

Current 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.

• Authors: Dongqiang Zeng, Jiani Wu, Huiyan Luo, Yong Li, Jian Xiao, Jianjun Peng, Zilan Ye, Rui Zhou, Yunfang Yu, Gaofeng Wang, Na Huang, Jianhua Wu, Xiaoxiang Rong, Li Sun, Huiying Sun, Wenjun Qiu, Yichen Xue, Jianping Bin, Yulin Liao, Nailin Li, Min Shi, Kyoung-Mee Kim, Wangjun Liao
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 9 Issue 8 (08 2021) ISSN: 2051-1426 [Electronic] England
• PMID: 34376552 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Chemical References

• Immune Checkpoint Inhibitors

Topics

• Adult
• Aged
• Computational Biology (methods)
• Female
• Humans
• Immune Checkpoint Inhibitors (pharmacology, therapeutic use)
• Immunotherapy (methods)
• Male
• Middle Aged
• Prospective Studies
• Stomach Neoplasms (drug therapy)
• Tumor Microenvironment