Angiopoietin-2/Tie2 signaling regulation of liver metastasis in pancreatic neuroendocrine tumors

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Liver metastases are found in nearly half of PanNET patients at diagnosis while many others develop liver metastasis after surgical resection of the primary tumor. Though the incidence of pancreatic neuroendocrine tumors (PanNET) has increased steadily over recent decades, there are only limited therapeutic options for metastatic PanNET patients. Furthermore, immune checkpoint inhibitors (ICI) showed the limited efficacy in patients with metastatic PanNET due to the immunosuppressive microenvironment. Therefore, understanding the mechanisms underlying liver metastasis, immune evasion, and their convergence on ICI therapy resistance in PanNET is urgently necessary to improve the clinical management of advanced PanNET. Vascular destabilization is recognized as a hallmark of tumor growth and metastasis. Angiopoietin-2 (Ang2), which binds to the receptor tyrosine kinase Tie2, is a potent vascular destabilizing factor. We demonstrated that under inflammatory conditions, Ang2 suppresses Tie2 signaling and promotes vascular destabilization and leakage. Importantly, emerging evidence suggests that vascular destabilization facilitates tumor immune evasion by impairing immune cell infiltration. In preliminary studies using a spontaneous PanNET mouse model, we found that Ang2 inhibition suppresses liver metastatic growth and improves the survival. Ang2 inhibition also reduced vascular leakage and increased CD8+ T-cell infiltration in metastases. We previously showed that suppression of Tie2 signaling is accompanied by ectodomain cleavage of the Tie2 coreceptor, Tie1, resulting in increased circulating levels of soluble Tie1 (sTie1). Our preliminary studies show that elevated plasma sTie1 levels in PanNET patients have significant prognostic implications. In this project, we will elucidate the mechanisms underlying Ang2-mediated liver metastatic progression, immunosuppression, and anti-PD-1 therapy resistance in metastatic PanNET. In Aim 1, we will determine the contribution of Ang2-mediated vascular destabilization to liver metastatic progression in PanNET by using human liver metastases and function-blocking antibodies or genetic Ang2 deletion in spontaneous and experimental PanNET mouse models. Mechanistically, in Aim 2, we will determine whether Ang2-mediated vascular leakage impairs CD8+ T-cell infiltration in liver metastases, serving as the basis for assessing the effects of Ang2 inhibition combined with anti-PD-1 therapy in metastatic PanNET. We will determine if Ang2 blockade sensitizes PanNET liver metastases to anti-PD-1 therapy by promoting vascular stabilization and CD8+ T-cell infiltration in PanNET mice. Finally, Aim 3 will identify circulating levels of sTie1 at diagnosis as a potential biomarker for tumor aggressiveness in PanNET patients. Successful completion of this project, which elucidates the mechanisms underlying vascular regulation of the immune evasion, could significantly enhance the clinical management of metastatic PanNET, as well as provide insights for the treatment of metastatic disease deriving from other tumor types, especially those with poor response to ICI therapy.