肿瘤细胞治疗研究
英文原题：Genetic and immune microenvironment characterization of HER2-positive gastric cancer: Their association with response to trastuzumab-based treatment.
对曲妥珠单抗反应良好的 HER2 阳性胃癌以细胞周期相关基因改变和 CD3 - CD57 + NK 细胞浸润增加为特征。
背景：本研究旨在确定与一线曲妥珠单抗治疗应答相关的HER2阳性胃癌（GC）分子特征及免疫微环境特征。方法：纳入83例接受曲妥珠单抗治疗的HER2阳性晚期胃腺癌患者。选取其中21例（探索队列）及2份治疗后样本进行靶向深度测序和转录组分析。比较治疗前6个月内进展的患者（第2组）与其他患者（第1组），并在总队列中采用荧光原位杂交（FISH）和免疫组织化学验证结果。利用RNA测序数据和多重免疫组织化学评估肿瘤浸润免疫细胞，并开展无进展生存期（PFS）分析。结果：第1组常见G1/S细胞周期检查点相关基因扩增，且细胞增殖相关KEGG通路上调。相比之下，第2组EGFR、HER3和MET扩增更常见，免疫相关KEGG通路RNA表达也高于第1组。在总队列中，PFS改善的显著预测因素包括细胞周期相关指标：CCNE1扩增、Cyclin A及PLK1过表达，以及Cyclin D3和HER3表达下降（p<0.05）；免疫相关指标包括CD3⁻CD57⁺ NK细胞密度高和PD-L1综合阳性评分（CPS）≥5（p<0.05）。Cyclin A、Cyclin E、p21和HER3组合是最佳预后预测指标（p<0.001）。结论：曲妥珠单抗应答良好的HER2阳性GC具有细胞周期相关基因改变和CD3⁻CD57⁺ NK细胞浸润增加等特征。这些发现有助于为HER2阳性GC患者制定更精准的治疗策略。
BACKGROUND: We aimed to determine the molecular and immune microenvironment characteristics of HER2-positive gastric cancer (GC) related to the patient's response to first-line trastuzumab-based treatment. METHODS: Eighty-three cases of HER2-positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post-treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor-infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression-free survival (PFS) analysis was performed. RESULTS: Group 1 showed frequent amplification of G1/S cell cycle checkpoint-related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune-related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle-related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p < 0.05), or immune-related including high density of CD3 - CD57 + NK cells and PD-L1 combined positive score 5 (p < 0.05). The best prognostic predictors were a combination of Cyclin A, Cyclin E, p21, and HER3 (p < 0.001). CONCLUSION: HER2-positive GC with favorable response to trastuzumab were characterized by cell cycle-related gene alterations and increased CD3 - CD57 + NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2-positive GC.
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