Kim Hyung-Don, Jung Seyoung, Bang Yeong Hak, Kim Jiae, Kim Hee Jeong, Lee Hyung Eun, Hyung Jaewon, Yoo Changhoon, Kim Won-Tae, Yoon Myeong-Jin, Lee Hayoung, Ryou Jeong-Hyun, Jeon Hyungsu, Yanai Hideyuki, Lee Jeong Seok, Lee Gwanghee, Ryu Min-Hee
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of).
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (the Republic of).
J Immunother Cancer. 2025 Mar 3;13(3):e010455. doi: 10.1136/jitc-2024-010455.
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.
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.
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 (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 expression and a positive correlation between its abundance and average 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).
Plasma TCTP is a prognostic biomarker, reflecting clinically relevant immunosuppressive myeloid signals in patients with gastric cancer.
目前尚无针对特定髓系细胞群或胃癌的既定生物标志物。本研究旨在探讨血浆翻译调控肿瘤蛋白（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及免疫学相关性。
前瞻性收集了接受一线氟嘧啶加铂类化疗的胃癌患者队列（n = 143，队列1）和三线纳武单抗治疗的患者队列（n = 165，队列2）的血浆样本。使用酶联免疫吸附测定（ELISA）对血浆TCTP水平进行定量，并进行多重蛋白质组分析（Olink）以评估免疫相关蛋白的表达水平。采用外部单细胞RNA测序（scRNA-seq）和空间转录组学数据集来验证研究结果。
与队列1中血浆TCTP水平低的患者（TCTP低组）相比，血浆TCTP水平高的患者（TCTP高组）一线化疗后的无进展生存期（PFS）和总生存期（OS）较差（PFS的风险比[HR]：1.73；OS的HR：1.77）。在TCTP高组中，与免疫抑制性髓系细胞、血管生成以及T/自然杀伤（NK）细胞功能的免疫排斥相关的蛋白上调，而在TCTP低组中，参与T细胞活化/耗竭的蛋白显著上调。scRNA-seq分析确定了一个高表达（编码TCTP）和TCTP相关分子的髓系亚群，富含抑制性髓系炎症基因特征并向T/NK细胞提供抑制信号（巨噬细胞趋化因子）。空间转录组学分析揭示了一个与巨噬细胞趋化因子亚群共定位的肿瘤细胞富集簇，其表现出最高的表达，并且其丰度与平均水平呈正相关。在接受纳武单抗治疗的患者（队列2）中，TCTP高组与较差的生存结果相关（PFS的HR：1.39；OS的HR：1.47）。
血浆TCTP是一种预后生物标志物，反映了胃癌患者临床上相关的免疫抑制性髓系信号。
