Project title: Targeting Angiopoietin-2 to Improve ICI Therapy Efficacy in pNET Metastasis

Description

Kim and her research team will induce vascular normalization and study the effectiveness of immune checkpoint inhibitor therapy in pancreatic NET liver metastases. The results of the research may have significant clinical implications for combination therapies that maximize anti-tumor immunity and therapeutic outcomes.

What question will the researchers try to answer?

Dr. Kim aims to understand the mechanisms underlying liver metastasis, immune evasion, and their convergence on current immunotherapy resistance in pancreatic neuroendocrine tumors (pNETs). 

Why is this important?

The incidence of pNETs has increased steadily over recent decades, and liver metastases are found in 40% of patients at diagnosis. Furthermore, following surgical tumor resection about 50% of patients with recurring pNETs undergo liver metastasis, which is associated with poor therapeutic outcomes. Lastly, the stimulation of anti-tumor immunity by treatment of immunotherapy such as checkpoint blockade has demonstrated limited treatment efficacy in pNET patients.

What will researchers do?

Dr. Kim and her team will study whether vascular destabilization in liver metastases contributes to metastatic progression in the liver, the most common site of distant metastasis in pNET. In this study, they will identify the mechanism underlying vascular regulation of immune suppression during metastatic progression and their convergence on immunotherapy resistance in pNET.

How might this improve the treatment of NETs?

By elucidating vascular regulation of immunosuppression in metastatic pNET, their work should offer new strategies to suppress liver metastatic progression and unleash the potential of immunotherapies for pNET patients. 

What is the next step?

Based on what they learn from the proposed work, her team will expand their research to learn vascular regulation of immunosuppression, liver metastasis, and therapeutic resistance by exploring human samples of pNET patients. In addition, they will identify potential predictive biomarkers (non-invasive) by testing the association of levels of circulating vascular molecules with treatment outcomes in patients who have pNETs.

Outcomes:

It is crucial to improve the management of metastasis in pancreatic neuroendocrine tumors (pNET) since nearly half of pNET patients present with liver metastases that account for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in the RNA-seq data from liver metastases of human pNET and found that a higher ANGPT2 expression correlated with poor survival rates. Our study revealed that ANGPT2 was restricted to the endothelial cells of blood vessels in pNET liver metastases. Upregulation of endothelial ANGPT2 had an association with liver metastatic progression in patients and transgenic mouse models with pNET. In human and mouse pNET liver metastases, ANGPT2 upregulation was accompanied by poor T-cell infiltration, consistent with an immunosuppressive tumor microenvironment. Importantly, both pharmacologic inhibition and genetic deletion of ANGPT2 in pNET mouse models slowed the growth of pNET liver metastases. Pharmacologic inhibition of ANGPT2 also promoted T-cell infiltration and activation in liver metastases and prolonged survival of mice with metastatic pNET. These changes coincided with reduced plasma leakage and improved vascular integrity in addition to alteration in chemokines regulating T-cell migration in metastases. Together, these findings provide evidence for ANGPT2 inhibition as a strategy for promoting T-cell infiltration and immunostimulatory reprogramming to reduce liver metastases in pNET.

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