Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, PR China.
Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, Xi'an Medical University, Xi'an, 710021, China.
Oncogene. 2022 Jun;41(24):3316-3327. doi: 10.1038/s41388-022-02298-7. Epub 2022 Apr 11.
GRB2-associated-binding protein 2 (Gab2) deletion has a preventive effect of on chronic liver inflammation and hepatocellular carcinoma. This study was aimed to elaborate Gab2-initiated immunoregulation during hepatocarcinogenesis. Compared to wild-type group, liver-specific overexpression of Gab2 mice (L-Gab2) displayed early hepatocarcinogenesis after 5-month diethylnitrosamine (DEN) induction, and accelerated tumor growth after 9-month DEN challenge. More myeloid-derived suppressor cells (MDSCs) were observed in DEN-challenged L-Gab2 mice than that in DEN-treated wild-type mice. Additionally, MDSCs activation-induced tumor angiogenesis capability and immunosuppression function were exceedingly activated in DEN-exposed L-Gab2 mice, which reflected in the increased platelet endothelial cell adhesion molecule (PECAM) and vascular endothelial growth factor (VEGF), and the decreased cytotoxic T lymphocytes. Mechanistically, DEN-challenged L-Gab2 mice produced more IL-6, and IL-6 depletion significantly deprived Gab2-overexpression-mediated tumor-promotion phenomena, accompanied by the impairment of MDSCs-initiated immunosuppression function. MDSCs isolated from IL-6-depleted L-Gab2 mice or inactivating MDSCs partly restored the immune function of cytotoxic T cells. Of note, MDSCs gene signatures had a significant association with the increased Gab2 or IL6 in hepatoma specimens. Collectively, L-Gab2 mice accelerated hepatoma progression possibly through activating IL-6-initiated the activation of MDSCs. This study provides a novel insights for exploring the role of Gab2 in autoimmune tolerance during hepatocarcinogenesis.
GRB2 相关结合蛋白 2 (Gab2) 的缺失对慢性肝炎症和肝细胞癌具有预防作用。本研究旨在阐述 Gab2 在肝癌发生过程中的起始免疫调节作用。与野生型组相比，肝特异性过表达 Gab2 小鼠 (L-Gab2) 在 5 个月 DEN 诱导后显示出早期肝癌发生，并且在 9 个月 DEN 挑战后加速肿瘤生长。在 DEN 处理的 L-Gab2 小鼠中观察到比 DEN 处理的野生型小鼠更多的髓系来源的抑制细胞 (MDSCs)。此外，在 DEN 暴露的 L-Gab2 小鼠中，MDSCs 激活诱导的肿瘤血管生成能力和免疫抑制功能被极度激活，这反映在血小板内皮细胞黏附分子 (PECAM) 和血管内皮生长因子 (VEGF) 的增加，以及细胞毒性 T 淋巴细胞的减少。在机制上，DEN 处理的 L-Gab2 小鼠产生了更多的 IL-6，并且 IL-6 耗竭显著剥夺了 Gab2 过表达介导的肿瘤促进现象，伴随着 MDSCs 起始的免疫抑制功能的损害。从 IL-6 耗竭的 L-Gab2 小鼠或失活的 MDSCs 中分离的 MDSCs 部分恢复了细胞毒性 T 细胞的免疫功能。值得注意的是，MDSCs 基因特征与肝癌标本中 Gab2 或 IL6 的增加有显著关联。总之，L-Gab2 小鼠可能通过激活 IL-6 诱导 MDSCs 的激活来加速肝癌的进展。这项研究为探索 Gab2 在肝癌发生过程中自身免疫耐受中的作用提供了新的见解。
