Intestinal Subtype as a Biomarker of Response to Neoadjuvant Immunochemotherapy in Locally Advanced Gastric Adenocarcinoma: Insights from a Prospective Phase II Trial

PURPOSE: Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma. 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 gastric adenocarcinoma with NAIC (NCT05515796). Correlation between clinicopathologic characteristics and neoadjuvant efficacy was investigated. Bulk RNA sequencing data from 104 samples (from 75 patients in two independent cohorts) and single-cell RNA sequencing data from 105 treatment-naïve gastric adenocarcinomas were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses. RESULTS: The prespecified primary endpoints were achieved: pathologic complete regression rate was 30%, major pathologic regression rate was 43%, and the regimen was well tolerated. Analysis of baseline clinical-pathologic 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-active cancer cells and enrichment of CLEC9A+ dendritic cells in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype gastric adenocarcinoma 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 DNA damage repair-active cancer cells and CLEC9A+ dendritic cells, which accurately predicted the efficacy of NAIC in multiple independent gastric adenocarcinoma cohorts. CONCLUSIONS: Intestinal subtype is a histologic biomarker of enhanced sensitivity of gastric adenocarcinoma to NAIC. The intestinal subtype-specific signature model is applicable to guide NAIC for patients with locally advanced gastric adenocarcinoma.