间皮素作为癌症免疫治疗的生物标志物和治疗靶点
Mesothelin as Biomarker and Therapeutic Target for Immunotherapy in Cancer.
癌症仍是一个关键的全球健康问题，原因在于发现晚、耐药和高死亡率。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
局部晚期胃癌肿瘤微环境特征刻画及与有益新辅助免疫化疗相关的空间预测性生物标志物鉴定
英文原题：Characterization of the tumor microenvironment in locally advanced gastric cancer and identification of spatially predictive biomarkers associated with beneficial neoadjuvant immunochemotherapy.
查看英文原题
Characterization of the tumor microenvironment in locally advanced gastric cancer and identification of spatially predictive biomarkers associated with beneficial neoadjuvant immunochemotherapy.
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研究概要
本研究确定了 NOTUM、SERPINA3 和 CD8+ T 细胞密度是 LAGC 中 nICT 反应的空间分辨、临床可操作的预测因子。我们的发现强调了空间 TME 探究在揭示新型生物标志物和指导个性化免疫治疗策略方面的力量。
研究思路结论见上方概要
背景
新辅助免疫化疗（nICT）已成为局部晚期胃癌（LAGC）的一种有前景的治疗策略，然而临床反应仍存在异质性，且缺乏可靠的预测性生物标志物。全面剖析肿瘤微环境（TME）对于揭示治疗疗效的决定因素并实现精准免疫治疗至关重要。
方法
我们使用NanoString GeoMx平台对19例接受替雷利珠单抗联合SOX化疗的LAGC患者治疗前内镜活检组织进行了数字空间分析（DSP）。多重荧光染色（PanCK、CD45、CD68）使得能够对肿瘤中心区域、免疫细胞浸润区域及其他间质区域进行区室特异性转录组分析。研究结果与TCGA-STAD数据整合，并在一个独立队列（n = 20）中通过免疫组化（IHC）对NOTUM、SERPINA3、CD8和FOXP3进行了验证。
结果
空间分析揭示了肿瘤中心区域（TC）、免疫细胞浸润区（MA）和其他基质区域（OTHER）区室之间存在不同的转录程序。肿瘤内在高表达 NOTUM、NKD1 和 SERPINA3，连同 TME 内 CD8 + T 细胞浸润升高和 Treg/CD3 + 比值降低，与主要病理缓解（MPR）稳健相关。这些空间生物标志物通过 IHC 在独立队列中进行了正交验证。在 TCGA-STAD 中，一个六基因特征（NOTUM、APOA2、SERPINA3、NKD1、GGH、BPIFB1）与延长生存和有利的免疫浸润相关，并在多种癌症类型中具有保守的免疫调节模式。
展开英文摘要原文
BACKGROUND
Neoadjuvant immunochemotherapy (nICT) has emerged as a promising strategy for locally advanced gastric cancer (LAGC), yet clinical responses remain heterogeneous and reliable predictive biomarkers are lacking. A comprehensive dissection of the tumor microenvironment (TME) is essential to uncover determinants of therapeutic efficacy and enable precision immunotherapy.
METHODS
We performed digital spatial profiling (DSP) using the NanoString GeoMx platform on pretreatment endoscopic biopsies from 19 LAGC patients treated with tislelizumab plus SOX chemotherapy. Multiplex fluorescence staining (PanCK, CD45, CD68) enabled compartment-specific transcriptomic analysis of tumor center regions, immune cell infiltration area, and other stromal regions. Findings were integrated with TCGA-STAD data and validated in an independent cohort (n = 20) by immunohistochemistry (IHC) for NOTUM, SERPINA3, CD8, and FOXP3.
RESULTS
Spatial profiling revealed distinct transcriptional programs across tumor-center regions (TC), immune cell infiltration area (MA), and other stromal regions (OTHER) compartments. High tumor-intrinsic expression of NOTUM, NKD1, and SERPINA3, together with elevated CD8 + T cell infiltration and a reduced Treg/CD3 + ratio within the TME, robustly associated with major pathological response (MPR). These spatial biomarkers were orthogonally validated by IHC in an independent cohort. In TCGA-STAD, a six-gene signature (NOTUM, APOA2, SERPINA3, NKD1, GGH, BPIFB1) correlated with prolonged survival and favorable immune infiltration, with conserved immune-modulatory patterns across multiple cancer types.
CONCLUSIONS
This study identifies NOTUM, SERPINA3, and CD8 + T cell density as spatially resolved, clinically actionable predictors of nICT response in LAGC. Our findings underscore the power of spatial TME interrogation to uncover novel biomarkers and guide personalized immunotherapeutic strategies.
论文信息
- 作者
- Xu X、Fan J、Peng L、Xiang Z、Luo D、Ma C、Huang B、Nie X
- 单位
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University ofScience and Technology, Wuhan, Hubei, China.China
- 期刊
- Frontiers in immunology2026
- 原文标识
- PubMed 42220510 · DOI 10.3389/fimmu.2026.1823308
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