肿瘤细胞治疗研究
英文原题：Molecular and immune determinants of response in locally advanced deficient DNA mismatch repair/microsatellite instability-high gastric or gastroesophageal junction adenocarcinoma treated with neoadjuvant chemoimmunotherapy.
NCIT 在 dMMR/MSI-H GAC/GEJAC 中取得了高缓解率和良好的生存结局。
背景：新辅助化学免疫治疗（NCIT）用于可切除的DNA错配修复缺陷/微卫星高度不稳定（dMMR/MSI-H）胃或胃食管结合部腺癌（GAC/GEJAC）显示出前景，但与疗效相关的生物标志物尚未充分明确。方法：研究分析了22例可切除dMMR/MSI-H GAC/GEJAC患者；患者围手术期接受信迪利单抗联合奥沙利铂和S-1（SOX）。通过影像、组织病理学、多组学和多重免疫组化评估临床应答、病理退缩、基因组改变和肿瘤微环境特征。结果：22例中，10例影像学部分缓解，客观缓解率为45.5%。17例接受手术，均实现R0切除。Becker肿瘤退缩分级1a、1b和2级分别见于10、1和6例，病理完全缓解率为58.8%（10/17）。2年无事件生存率和总生存率分别为81.8%和80.7%。未应答者生存较差，基线肿瘤内异质性更高，且NF1、KDR、CDKN2A和PLK1突变富集。转录组分析显示，应答者中GYLTL1B、PHLDA1、IGFN1和SH2D5显著上调，同时增殖相关通路（E2F、MYC靶基因）及免疫刺激通路（TNFA经NFKB介导的通路、IFN应答）被激活。相反，未应答者缺少这些转录特征，并呈现免疫抑制特征，包括甲基化TIL（肿瘤浸润淋巴细胞）（MeTIL）和辅助性T细胞17（Th17）特征表达升高，以及M1巨噬细胞浸润增加。治疗后，应答者出现有利的免疫重塑，表现为M1巨噬细胞减少、树突状细胞和NK细胞群体增加；未应答者免疫变化有限，但M1巨噬细胞持续偏高。部分生物标志物，包括CDKN2A突变、范可尼贫血通路改变及特定转录组特征，与治疗应答和预后均相关。结论：NCIT治疗dMMR/MSI-H GAC/GEJAC取得较高应答率和良好生存结果。这些发现凸显分子指导的风险分层有望更准确预测该人群的治疗应答，并支持制定个体化治疗策略。
BACKGROUND: Neoadjuvant chemoimmunotherapy (NCIT) shows promise for resectable deficient DNA mismatch repair/microsatellite instability-high (dMMR/MSI-H) gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). However, biomarkers associated with treatment response remain inadequately defined. METHODS: We analyzed 22 patients with resectable dMMR/MSI-H GAC/GEJAC treated with perioperative sintilimab plus oxaliplatin and S-1 (SOX). Clinical response, pathological regression, genomic alterations, and tumor microenvironment characteristics were assessed using imaging, histopathology, multi-omics, and multiplex immunohistochemistry. RESULTS: Of the 22 patients, radiological partial response was observed in 10, yielding an objective response rate of 45.5%. Seventeen patients underwent surgery, all achieving R0 resection. Becker tumor regression grades 1a, 1b, and 2 were observed in 10, 1, and 6 patients, respectively, corresponding to a pathological complete response rate of 58.8% (10/17). Two-year event-free and overall survival rates were 81.8% and 80.7%, respectively. Non-responders demonstrated worse survival and higher baseline intratumor heterogeneity, with enriched mutations in NF1, KDR, CDKN2A, and PLK1. Transcriptomic analysis revealed significant upregulation of GYLTL1B, PHLDA1, IGFN1, and SH2D5 in responders, along with activation of proliferative (E2F, MYC targets) and immune-stimulatory (TNFA via NFKB, IFN responses) pathways. Conversely, non-responders lacked these transcriptional signatures and displayed immunosuppressive features, including elevated methylated tumor-infiltrating lymphocytes (MeTIL) and T helper 17 (Th17) signature expression and increased infiltration of M1 macrophages. Post-treatment analysis showed favorable immune remodeling in responders, characterized by reduced M1 macrophages and increased dendritic and NK cell populations. Non-responders, however, exhibited minimal immune shifts but persistent M1 macrophage elevation. Certain biomarkers, including CDKN2A mutations, Fanconi anemia pathway alterations, and specific transcriptomic signatures, were found to correlate with both treatment response and prognosis. CONCLUSIONS: NCIT achieved high response rates and favorable survival outcomes in dMMR/MSI-H GAC/GEJAC. These findings underscore the potential of molecular-guided risk stratification to better predict treatment responses and personalized therapeutic strategies in this patient population.
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