PO.CL01.02 · 临床研究
dMMR/MSI-H胃癌新辅助化学免疫治疗应答的临床与免疫相关因素
Clinical and immune correlates of response to neoadjuvant chemoimmunotherapy in dMMR/MSI-H gastric cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：新辅助化学免疫治疗（NCIT）在可切除的DNA错配修复缺陷/微卫星高度不稳定（dMMR/MSI-H）胃癌或胃食管结合部腺癌（GAC/GEJAC）中显示出良好的疗效，但预测应答的生物标志物仍不明确。
方法：我们分析了22例接受围手术期sintilimab联合奥沙利铂和S-1（SOX）治疗的可切除dMMR/MSI-H GAC/GEJAC患者。通过影像学、组织病理学、多组学分析及多重免疫组化对临床应答、病理消退、基因组改变和肿瘤微环境（TME）特征进行了刻画。根据影像学和病理学评估将患者分为应答者与非应答者。
结果：22例患者中10例（45.5%）实现了影像学部分缓解。17例接受了R0切除，Becker肿瘤消退分级为1a、1b和2的病例分别为10例、1例和6例，病理完全缓解率为58.8%。两年无事件生存率和总生存率分别为81.8%和80.7%。非应答者生存较差，基线瘤内异质性更大，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上调，并伴有增殖相关（E2F、MYC靶点）和免疫刺激性（TNFA-NFKB、干扰素）通路的激活。相反，非应答者缺乏这些特征，并表现出免疫抑制性TME特征，包括甲基化肿瘤浸润淋巴细胞升高、Th17特征表达和M1巨噬细胞浸润。治疗后分析显示应答者出现良好的免疫重塑，表现为树突状细胞和NK细胞增加、M1巨噬细胞减少，而非应答者维持以M1为主的状态。CDKN2A突变、范可尼贫血通路改变及特定转录组特征等预测性生物标志物与应答和预后均相关。
结论：NCIT在dMMR/MSI-H GAC/GEJAC中带来了较高的病理应答率和生存率。整合分子与免疫分析识别出应答的基因组和转录组决定因素，为该分子定义队列中生物标志物指导的治疗策略提供了支持。
查看英文原文 English abstract
Background: Neoadjuvant chemoimmunotherapy (NCIT) has shown promising efficacy in resectable deficient DNA mismatch repair/microsatellite instability-high (dMMR/MSI-H) gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC), yet predictive biomarkers of response remain unclear.
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 (TME) features were characterized by imaging, histopathology, multi-omics profiling, and multiplex immunohistochemistry. Patients were classified as responders or non-responders based on radiological and pathological evaluations.
Results: Radiological partial response was achieved in 10 of 22 patients (45.5%). Seventeen underwent R0 resection, with Becker tumor regression grades 1a, 1b, and 2 in 10, 1, and 6 cases, yielding a pathological complete response rate of 58.8%. Two-year event-free and overall survival were 81.8% and 80.7%. Non-responders exhibited poorer survival and greater baseline intratumor heterogeneity, with enriched mutations in NF1 , KDR , CDKN2A , and PLK1 . Transcriptomic profiling revealed upregulation of GYLTL1B , PHLDA1 , IGFN1 , and SH2D5 in responders, alongside activation of proliferative (E2F, MYC targets) and immune-stimulatory (TNFA-NFKB, interferon) pathways. In contrast, non-responders lacked these signatures and showed immunosuppressive TME features, including elevated methylated tumor-infiltrating lymphocytes, Th17 signature expression, and M1 macrophage infiltration. Post-treatment analysis indicated favorable immune remodeling in responders, marked by increased dendritic and NK cells and decreased M1 macrophages, while non-responders maintained an M1-dominant state. Predictive biomarkers such as CDKN2A mutation, Fanconi anemia pathway alteration, and specific transcriptomic signatures correlated with both response and prognosis.
Conclusions: NCIT yielded high pathological response and survival rates in dMMR/MSI-H GAC/GEJAC. Integrated molecular and immune profiling identified genomic and transcriptomic determinants of response, supporting biomarker-guided therapeutic strategies in this molecularly defined cohort.
利益披露 Disclosure
P. Yu, None..
X. Huang, None..
X. Chen, None..
H. Chen, None.
S. Wang,
Nanjing Geneseeq Technology Inc. Employment.
D. Wang,
Nanjing Geneseeq Technology Inc. Employment.
J. Yan,
Nanjing Geneseeq Technology Inc. Employment.
J. Chen, None..
Q. Wei, None..
Z. Wu, None..
S. Fang, None..
H. Chen, None..
H. Wang, None..
C. Zhu, None..
L. Huang, None..
Y. Du, None.
H. Bao,
Nanjing Geneseeq Technology Inc. Employment.
H. Tang,
Nanjing Geneseeq Technology Inc. Employment.
X. Wu,
Nanjing Geneseeq Technology Inc. Employment.
X. Cheng, None.