Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase II trial

• Published in: Clinical cancer research
• Main Authors: Wang, Lei, Sun, Mengting, Li, Jinyang, Wan, Linghong, Tan, Yuting, Tian, Shuoran, Hou, Yongying, Wu, Linyu, Peng, Ziyi, Hu, Xiao, Zhang, Qihua, Huang, Zening, Han, Mengyi, Peng, Shiyin, Pan, Yuwei, Ren, Yuanfeng, Zhang, Mengsi, Chen, Dongfeng, Liu, Qin, Li, Xianfeng, Qin, Zhong-yi, Xiang, Junyv, Li, Mengxia, Zhu, Jianwu, Chen, Qiyue, Luo, Huiyan, Wang, Shunan, Wang, Tao, Li, Fan, Bian, Xiu-wu, Wang, Bin
• Format: Journal Article
• Language: English
• Published: 04-11-2024
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-24-2436

Purpose:Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma (GAC). However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC. Patients and Methods: A prospective, single-arm, phase II study was conducted to treat locally advanced GAC with NAIC (NCT05515796). Correlation between clinicopathological characteristics and neoadjuvant efficacy was investigated. Bulk RNA-seq data from 104 samples (from 75 patients in two independent cohorts) and scRNA-seq data from 105 treatment-naïve GACs were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses. Results: The pre-specified primary endpoints were achieved: pathological complete regression (pathCR) rate was 30%, major pathological regression (MPR) rate was 43%, while the regimen was well tolerated. Analysis of baseline clinical-pathological parameters revealed the intestinal subtype of Lauren’s classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair (DDR)-active cancer cells and enrichment of CLEC9A+ dendritic cells (DCs) in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype GAC to NAIC. More importantly, an intestinal-subtype specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DDR-active cancer cells and CLEC9A+ DCs, which accurately predicted the efficacy of NAIC in multiple independent GAC cohorts. Conclusions: Intestinal subtype is a histological biomarker of enhanced sensitivity of GAC to NAIC. The Intestinal-subtype specific signature model is applicable to guide NAIC for patients with locally advanced GAC.