Department of Oncology, The First People's Hospital Affiliated to Yangtze University, Jingzhou City, Hubei Province 434000, China.
Department of Oncology, The First People's Hospital Affiliated to Yangtze University, Jingzhou City, Hubei Province 434000, China.
Int J Biochem Cell Biol. 2024 Sep;174:106621. doi: 10.1016/j.biocel.2024.106621.
Immune escape is a major obstacle to T-cell-based immunotherapy for cancers such as gastric cancer (GC). Mesoderm-specific transcript (MEST) is a tumor-promoting factor that regulates multiple oncogenic signaling pathways. However, the role of MEST-mediated immune escape is unclear.
Bioinformatics analysis of MEST expression and enrichment pathways were performed Quantitative reverse transcription PCR (qPCR) or western blot was used to detect the expression of MEST, Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), Major histocompatibility class I (MHCI)-related genes. Cell function was assessed by Cell Counting Kit (CCK)-8, Transwell, Lactate dehydrogenase (LDH) kit, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC). Xenograft nude mice and immune-reconstructed mice were used to test the effects of different treatments on tumor growth and immune escape in vivo.
MEST was upregulated in GC and promoted tumor proliferation, migration, and invasion. Rescue experiments revealed that TNO155 treatment or knockdown of SHP2 promoted the killing ability of CD8 T cells and the expression of granzyme B (GZMB) and interferon-gamma (IFN-γ), and MEST overexpression reversed the effect. In vivo experiments confirmed that MEST promoted tumor growth, knockdown of MEST inhibited immune escape in GC, and that combination treatment with anti-PD-1 improved anti-tumor activity.
In this study, we demonstrated that MEST inhibited IFN-γ secretion from CD8+ T cells by up-regulating SHP2, thereby downregulating MHCI expression in GC cells to promote immune escape and providing a new T cell-based therapeutic potential for GC.
免疫逃逸是基于 T 细胞的癌症免疫疗法（如胃癌（GC））的主要障碍。中胚层特异性转录物（MEST）是一种促进肿瘤的因子，可调节多种致癌信号通路。然而，MEST 介导的免疫逃逸的作用尚不清楚。
对 MEST 表达和富集途径进行生物信息学分析，采用定量逆转录聚合酶链反应（qPCR）或 Western blot 检测 MEST、Src 同源结构域 2 含蛋白酪氨酸磷酸酶 2（SHP2）、主要组织相容性复合体 I（MHCI）相关基因的表达。通过细胞计数试剂盒（CCK）-8、Transwell、乳酸脱氢酶（LDH）试剂盒、流式细胞术、酶联免疫吸附测定（ELISA）和免疫组织化学（IHC）评估细胞功能。使用异种移植裸鼠和免疫重建小鼠在体内测试不同治疗方法对肿瘤生长和免疫逃逸的影响。
MEST 在 GC 中上调，并促进肿瘤增殖、迁移和侵袭。挽救实验表明，TNO155 治疗或 SHP2 敲低促进 CD8 T 细胞的杀伤能力和颗粒酶 B（GZMB）和干扰素-γ（IFN-γ）的表达，而 MEST 的过表达则逆转了这种作用。体内实验证实，MEST 促进肿瘤生长，敲低 MEST 抑制 GC 中的免疫逃逸，联合使用抗 PD-1 可提高抗肿瘤活性。
在这项研究中，我们证明了 MEST 通过上调 SHP2 抑制 CD8+T 细胞中 IFN-γ的分泌，从而下调 GC 细胞中 MHCI 的表达，促进免疫逃逸，并为 GC 提供了一种新的基于 T 细胞的治疗潜力。
