Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment.
Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment.
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DOI：
10.1172/jci167994
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发表时间：
2023-10-16
影响因子：
15.9
通讯作者：
Kim, Minah
中科院分区：
文献类型：
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作者：
Lee, Eunhyeong;O'Keefe, Sophie;Leong, Alessandra;Park, Ha-Ram;Varadarajan, Janani;Chowdhury, Subrata;Hiner, Shannon;Kim, Sungsoo;Shiva, Anahita;Friedman, Richard A.;Remotti, Helen;Fojo, Tito;Yang, Hee Won;Thurston, Gavin;Kim, Minah
改善胰腺神经内分泌肿瘤(PanNETs)的转移管理至关重要，因为近一半的PanNETs患者存在肝转移，这是导致大部分患者死亡的原因。我们发现血管生成素-2(Angiopoietin-2，ANGPT2)是来自人全肝转移瘤的RNA-Seq数据中最上调的血管生成因子之一，并且发现ANGPT2的高表达与较低的生存率相关。免疫组织化学染色显示，ANGPT2定位于全肝转移瘤血管内皮细胞。我们观察到在两个患者和PanNETs转基因小鼠模型中，内皮ANGPT2的上调与肝转移进展之间存在关联。在人类和小鼠全肝转移中，ANGPT2表达上调与T细胞浸润不良相一致，这表明肿瘤微环境处于免疫抑制状态。值得注意的是，在Pannet小鼠模型中，药物抑制和ANGPT2基因缺失都减缓了Pannet肝转移的生长。此外，ANGPT2的药理抑制促进了T细胞在肝转移瘤中的渗透和激活，提高了转移的PanNETs小鼠的存活率。这些变化伴随着转移瘤中血浆渗漏的减少和血管完整性的改善。综上所述，这些发现表明，阻断ANGPT2可能是一种有效的策略，可以促进T细胞的渗透和免疫刺激重编程，以减少PanNET中肝转移的生长。
Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in RNA-Seq data from human PanNET liver metastases and found that higher ANGPT2 expression correlated with poor survival rates. Immunohistochemical staining revealed that ANGPT2 was localized to the endothelial cells of blood vessels in PanNET liver metastases. We observed an association between the upregulation of endothelial ANGPT2 and liver metastatic progression in both patients and transgenic mouse models of PanNETs. In human and mouse PanNET liver metastases, ANGPT2 upregulation coincided with poor T cell infiltration, indicative of an immunosuppressive tumor microenvironment. Notably, both pharmacologic inhibition and genetic deletion of ANGPT2 in PanNET mouse models slowed the growth of PanNET liver metastases. Furthermore, pharmacologic inhibition of ANGPT2 promoted T cell infiltration and activation in liver metastases, improving the survival of mice with metastatic PanNETs. These changes were accompanied by reduced plasma leakage and improved vascular integrity in metastases. Together, these findings suggest that ANGPT2 blockade may be an effective strategy for promoting T cell infiltration and immunostimulatory reprogramming to reduce the growth of liver metastases in PanNETs.