Blood TCTP as a potential biomarker associated with immunosuppressive features and poor clinical outcomes in metastatic gastric cancer.

IF 10.3 1区医学 Q1 IMMUNOLOGY

Journal for Immunotherapy of Cancer Pub Date : 2025-03-03 DOI:10.1136/jitc-2024-010455

Hyung-Don Kim, Seyoung Jung, Yeong Hak Bang, Jiae Kim, Hee Jeong Kim, Hyung Eun Lee, Jaewon Hyung, Changhoon Yoo, Won-Tae Kim, Myeong-Jin Yoon, Hayoung Lee, Jeong-Hyun Ryou, Hyungsu Jeon, Hideyuki Yanai, Jeong Seok Lee, Gwanghee Lee, Min-Hee Ryu

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引用次数: 0

Abstract

Background: No established biomarker exists for specific myeloid cell populations or in gastric cancer. This study aimed to explore the prognostic and immunological relevance of plasma translationally controlled tumor protein (TCTP) in patients with advanced gastric cancer treated with an immune checkpoint inhibitor and/or cytotoxic chemotherapy.

Methods: Plasma samples were prospectively collected from the cohorts of patients with gastric cancer treated with first-line fluoropyrimidine plus platinum chemotherapy (n=143, cohort 1) and third-line nivolumab (n=165, cohort 2). Plasma TCTP levels were quantified using ELISA, and multiplex proteomic analysis (Olink) was conducted to assess expression levels of immune-related proteins. External single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics datasets were employed to validate the findings.

Results: Patients with high plasma TCTP levels (TCTP-high group) exhibited poor progression-free survival (PFS) and overall survival (OS) with first-line chemotherapy compared with those with low levels (TCTP-low group) in cohort 1 (HR: 1.73 for PFS; 1.77 for OS). In the TCTP-high group, proteins associated with immunosuppressive myeloid cells, angiogenesis, and immune exclusion of T/natural killer (NK) cell function were upregulated, whereas proteins involved in T-cell activation/exhaustion were significantly upregulated in the TCTP-low group. scRNA-seq analyses identified a myeloid subset with high TPT1 (encoding TCTP) expression and TCTP-related molecules, enriched with inhibitory myeloid inflammation gene signatures and providing inhibitory signals to T/NK cells (Macrophage-chemokine). Spatial transcriptomics analyses revealed a tumor-cell-enriched cluster co-localized with the Macrophage-chemokine subset, which exhibited the highest TPT1 expression and a positive correlation between its abundance and average TPT1 levels. In nivolumab-treated patients (cohort 2), the high TCTP group was associated with poor survival outcomes (HR: 1.39 for PFS; 1.47 for OS).

Conclusions: Plasma TCTP is a prognostic biomarker, reflecting clinically relevant immunosuppressive myeloid signals in patients with gastric cancer.

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血液 TCTP 是与转移性胃癌的免疫抑制特征和不良临床预后相关的潜在生物标记物。

背景：没有确定的生物标志物存在于特定的骨髓细胞群或胃癌中。本研究旨在探讨血浆翻译控制肿瘤蛋白（TCTP）在接受免疫检查点抑制剂和/或细胞毒性化疗的晚期胃癌患者中的预后和免疫学相关性。方法：前瞻性收集一线氟嘧啶加铂化疗（n=143，队列1）和三线纳武单抗（n=165，队列2）胃癌患者的血浆样本，采用ELISA定量血浆TCTP水平，并采用多重蛋白质组学分析（Olink）评估免疫相关蛋白的表达水平。外部单细胞RNA测序（scRNA-seq）和空间转录组学数据集被用来验证这些发现。结果：在队列1中，血浆TCTP水平高的患者（TCTP高组）与血浆TCTP水平低的患者（TCTP低组）相比，一线化疗的无进展生存期（PFS）和总生存期（OS）较差(HR: 1.73；1.77操作系统)。在tcpp高的组中，与免疫抑制髓细胞、血管生成和免疫排斥T/自然杀伤细胞（NK）功能相关的蛋白上调，而在tcpp低的组中，与T细胞激活/衰竭相关的蛋白显著上调。scRNA-seq分析发现一个髓系亚群具有高TPT1（编码TCTP）表达和TCTP相关分子，富含抑制性髓系炎症基因特征，并向T/NK细胞（巨噬细胞趋化因子）提供抑制信号。空间转录组学分析显示，肿瘤细胞富集簇与巨噬细胞趋化因子亚群共定位，TPT1表达量最高，其丰度与TPT1平均水平呈正相关。在尼伏单抗治疗的患者（队列2）中，高TCTP组与较差的生存结果相关(PFS的HR: 1.39；操作系统1.47)。结论：血浆TCTP是一种预后生物标志物，反映胃癌患者临床相关的免疫抑制髓系信号。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

17.70

自引率

4.60%

发文量

522

审稿时长

18 weeks

期刊介绍： The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.