PO.CL01.06 · 临床研究

一种基于循环GPNMB的多模态模型整合肿瘤-免疫串扰以预测食管癌免疫治疗应答

A circulating GPNMB-based multimodal model integrates tumor-immune crosstalk to predict immunotherapy response in esophageal cancer

编号 7724 展板 15 时间 4/22 09:00–12:00 区域 Section 41 主讲 Chen Wu, PhD

分会场 Biomarkers Predictive of Therapeutic Benefit 6

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作者与单位 Authors & Affiliations

Liang Zhu¹, Xiaoyuan Wang², Guoyu Cheng¹, Yancheng Lai¹, Lan Lan¹, Zhenghao Dong¹, Zhixuan You¹, Xinjie Chen¹, Ziyi He¹, Xinyi Xiao¹, Lingxuan Zhu¹, Rucheng Liu¹, Shaosen Zhang¹, Dongxin Lin¹, Chen Wu¹, Jiang Chang³

¹Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China,²Harbin Medical University Cancer Hospital, Harbin, China,³Department of Epidemiology and Biostatistics, Huazhong University of Science & Technology, Wuhan, China

摘要 Abstract

中文摘要

新辅助免疫治疗改善了食管鳞状细胞癌（ESCC）的结局，但约70%的患者未能应答。因此，治疗前活检和血浆为生物标志物发现提供了关键机会。在此，我们进行了血浆蛋白质组学分析，并鉴定出可溶性非转移性黑色素瘤糖蛋白B（sGPNMB）是无应答者中升高最显著的循环蛋白。机制上，肿瘤细胞来源的sGPNMB抑制CD8+ T细胞受体（TCR）信号传导以诱导功能性耗竭，其免疫抑制活性依赖于分泌。癌症相关成纤维细胞-上皮（CAF-Epi）微环境促进肿瘤细胞中SOX2上调，从而转录激活GPNMB表达。在人源化PDX模型中，血浆GPNMB水平可预测对PD-1阻断的应答，且GPNMB抑制与治疗协同增效。在多个回顾性队列和一项前瞻性临床试验中，一个结合血浆GPNMB水平、CAF-Epi微环境检测和临床病理特征的多模态模型，对免疫治疗应答和生存率实现了稳健的预测准确性。这些发现为ESCC的精准免疫治疗建立了一个以机制为基础的空间-循环生物标志物框架。

查看英文原文 English abstract

Neoadjuvant immunotherapy improves outcomes in esophageal squamous cell carcinoma (ESCC), yet ~70% of patients fail to respond. Pretreatment biopsies and plasma thus provide critical opportunities for biomarker discovery. Here, we performed plasma proteomic profiling and identified soluble glycoprotein non-metastatic melanoma protein B (sGPNMB) as the most elevated circulating protein in non-responders. Mechanistically, tumor cell-derived sGPNMB suppressed CD8 + T cell receptor (TCR) signaling to induce functional exhaustion, with secretion being required for its immunosuppressive activity. Cancer-associated fibroblast-epithelial (CAF-Epi) niches promoted SOX2 upregulation in tumor cells, transcriptionally activating GPNMB expression. In humanized PDX models, plasma GPNMB levels predicted response to PD-1 blockade, and GPNMB inhibition synergised with therapy. Across retrospective cohorts and a prospective clinical trial, a multimodal model combining plasma GPNMB levels, CAF-Epi niche detection, and clinical-pathological features achieved robust predictive accuracy for immunotherapy response and survival. These findings establish a mechanistically grounded, spatial-circulating biomarker framework for precision immunotherapy in ESCC.

利益披露 Disclosure

L. Zhu, None.. X. Wang, None.. G. Cheng, None.. Y. Lai, None.. L. Lan, None.. Z. Dong, None.. Z. You, None.. X. Chen, None.. Z. He, None.. X. Xiao, None.. L. Zhu, None.. R. Liu, None.. S. Zhang, None.. D. Lin, None.. C. Wu, None.

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