PO.CL01.04 · 临床研究
在11q13扩增的中国食管癌中，免疫微环境而非基因组改变驱动超进展相关特征
Immune microenvironment rather than genomic alterations drives hyperprogression-related features in 11q13 amplified Chinese esophageal cancer
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摘要 Abstract
中文摘要
背景：免疫检查点抑制剂(ICIs)已改变了食管癌(ESCA)的治疗格局，然而一部分患者在免疫治疗后出现超进展性疾病(HPD)。既往研究提示，位于11q13染色体上的基因组改变——包括CCND1、FGF3、FGF4和FGF19的扩增——可能与HPD相关。本研究旨在探讨ESCA中11q13扩增是否与基因组特征或独特的免疫微环境特征相关，从而有助于解释免疫治疗耐药及HPD的发生。
方法：采用733基因二代测序(NGS)panel对341例ESCA患者的肿瘤样本进行分析，以刻画基因组特征，包括DDR通路改变、肿瘤突变负荷(TMB)和瘤内异质性(ITH)。同时进行多重免疫荧光(mIF)以评估关键免疫微环境组分。就基因组改变和免疫细胞浸润比较有和无11q13扩增的患者。
结果：在341例ESCA患者中，49.3%(168/341)存在11q13扩增。基因组分析显示，11q13扩增组与非扩增组在DDR通路基因改变、TMB或ITH方面无显著差异，提示11q13相关的免疫治疗耐药不太可能由内在基因组不稳定性驱动。相比之下，免疫微环境分析显示出显著差异：11q13扩增的患者在肿瘤间质中FOXP3⁺调节性T细胞(P=0.005)和CD3⁺CD4⁺FOXP3⁺ T细胞(P=0.03)的浸润显著减少，而在肿瘤实质中CD8⁺PD-1⁺ T细胞的浸润和密度显著增加(密度P=0.01；阳性率P=0.02)。这些免疫模式与既往报道的HPD相关特征一致，提示在11q13扩增的ESCA中，免疫失调而非基因组改变可能是超进展的基础。
结论：ESCA中11q13扩增与DDR基因改变、TMB或ITH无相关性，但与既往关联于HPD的独特免疫微环境特征密切相关，包括间质调节性T细胞浸润减少和实质CD8⁺PD-1⁺ T细胞增加。这些发现凸显了免疫微环境失调在11q13扩增ESCA中的临床重要性，并强调了针对该分子亚组制定个体化治疗策略的必要性。
查看英文原文 English abstract
Background: Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of esophageal cancer (ESCA), yet a subset of patients experience hyperprogressive disease (HPD) following immunotherapy. Previous studies have suggested that genomic alterations located on chromosome 11q13-including amplification of CCND1, FGF3, FGF4, and FGF19-may contribute to HPD. This study aimed to investigate whether 11q13 amplification in ESCA is associated with genomic features or distinct immune microenvironment characteristics that could help explain resistance to immunotherapy and the development of HPD.
Methods: Tumor samples from 341 ESCA patients were analyzed using a 733-gene next-generation sequencing (NGS) panel to characterize genomic profiles, including DDR pathway alterations, tumor mutation burden (TMB), and intratumor heterogeneity (ITH). Multiplex immunofluorescence (mIF) was also performed to evaluate key immune microenvironment components. Patients with and without 11q13 amplification were compared with respect to genomic alterations and immune cell infiltration.
Results: Among the 341 ESCA patients, 49.3% (168/341) exhibited 11q13 amplification. Genomic analysis revealed no significant differences between the 11q13-amplified and non-amplified groups in DDR pathway gene alterations, TMB, or ITH, suggesting that 11q13-associated immunotherapy resistance is unlikely to be driven by intrinsic genomic instability. In contrast, immune microenvironment profiling demonstrated marked differences: patients with 11q13 amplification exhibited significantly reduced infiltration of FOXP3⁺ regulatory T cells (P=0.005) and CD3⁺CD4⁺FOXP3⁺ T cells (P=0.03) in the tumor stroma, while showing significantly increased infiltration and density of CD8⁺PD-1⁺ T cells in the tumor parenchyma (P=0.01 for density; P=0.02 for positivity). These immune patterns are consistent with previously reported features associated with HPD, suggesting that immune dysregulation rather than genomic alterations may underlie hyperprogression in 11q13-amplified ESCA.
Conclusion: 11q13 amplification in ESCA does not correlate with DDR gene alterations, TMB, or ITH, but is strongly associated with distinct immune microenvironment features previously linked to HPD, including reduced stromal regulatory T cell infiltration and increased parenchymal CD8⁺PD-1⁺ T cell presence. These findings highlight the clinical importance of immune microenvironment dysregulation in 11q13-amplified ESCA and underscore the need for tailored therapeutic strategies for this molecular subgroup.
利益披露 Disclosure
L. Deng, None.