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.

中文翻译：

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肠道亚型作为局部晚期胃腺癌对新辅助免疫化疗反应的生物标志物：来自前瞻性 II 期试验的见解


目的： 新辅助免疫化疗 （NAIC） 显著诱导局部晚期胃腺癌 （GAC） 的病理消退。然而，仍然缺乏特异性生物标志物来有效识别 NAIC 的受益患者。患者和方法： 进行了一项前瞻性、单臂、II 期研究，以使用 NAIC 治疗局部晚期 GAC （NCT05515796。调查临床病理特征与新辅助疗效之间的相关性。全面分析了来自 104 个样本（来自两个独立队列中的 75 名患者）的大量 RNA-seq 数据和来自 105 个未接受过治疗的 GAC 的 scRNA-seq 数据，以破译上皮和微环境特征与临床反应之间的关联。结果： 达到预先设定的主要终点： 病理完全回归 （pathCR） 率为 30%，主要病理消退 （MPR） 率为 43%，而方案耐受性良好。基线临床病理参数分析显示，Lauren 分类的肠道亚型是对 NAIC 敏感性增加的患者进行分层的关键特征。从机制上讲，肿瘤微环境中 DNA 损伤修复 （DDR） 活性癌细胞库的增加和 CLEC9A+ 树突状细胞 （DC） 的富集与肠道亚型 GAC 对 NAIC 的反应性增强有关。更重要的是，机器学习算法 NaiveBayes 通过整合 DDR 活性癌细胞和 CLEC9A+ DC 的转录组学特征，构建了肠道亚型特异性特征模型，准确预测了 NAIC 在多个独立 GAC 队列中的疗效。结论： 肠道亚型是 GAC 对 NAIC 敏感性增强的组织学生物标志物。 肠道亚型特异性特征模型适用于指导局部晚期 GAC 患者的 NAIC。