Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment
Eunhyeong Lee, … , Gavin Thurston, Minah Kim
Eunhyeong Lee, … , Gavin Thurston, Minah Kim
Published October 16, 2023
Citation Information: J Clin Invest. 2023;133(20):e167994. https://doi.org/10.1172/JCI167994.
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Research Article Angiogenesis

Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment

Abstract

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.

Authors

Eunhyeong Lee, Sophie O’Keefe, Alessandra Leong, Ha-Ram Park, Janani Varadarajan, Subrata Chowdhury, Shannon Hiner, Sungsoo Kim, Anahita Shiva, Richard A. Friedman, Helen Remotti, Tito Fojo, Hee Won Yang, Gavin Thurston, Minah Kim

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Figure 5

T cells mediate the antimetastatic response of ANGPT2 blockade.

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T cells mediate the antimetastatic response of ANGPT2 blockade. (A) Expe...
(A) Experimental timeline for SCID mice injected with 99-3o or AJ-5257-1 cells. (B–E) Whole-liver-lobe cross-sections comparing metastatic burden in 99-3o cell–injected (scale bar: 1 mm) (B) or AJ-5257-1 cell–injected (scale bar: 1 mm) (D) SCID mice treated with IgG or anti-ANGPT2, and the corresponding quantifications of SV40 T-antigen+ metastatic burden (unpaired t test) (C and E). (F and G) Expression of cleaved caspase-3 in 20-week-old RT2;AB6F1 mice treated with IgG (top) or anti-ANGPT2 (bottom) (scale bar: 50 μm) (F) and its quantification (unpaired t test) (G). (H–K) Expression of fibrin (scale bar: 50 μm) (H) and VE-cadherin (scale bar: 50 μm) (J) in 20-week-old RT2;AB6F1 mice treated with IgG or anti-ANGPT2 and quantification of vascular leakage (I) and VE-cadherin coverage (K) (unpaired t test). (L) Experimental timeline of CD8+ or CD4+ T cell depletion study in which RT2;AB6F1 mice were treated with IgG, anti-ANGPT2, and combination of anti-ANGPT2 with anti-CD8 or anti-CD4 antibodies beginning at 18 weeks of age. (M and N) Whole-liver-lobe cross-sections comparing metastatic burden in RT2;AB6F1 mice treated with IgG, anti-ANGPT2, and combination of anti-ANGPT2 with anti-CD8 or anti-CD4 antibodies (scale bar: 1 mm) (M) and quantification of SV40 T-antigen+ metastatic burden (1-way ANOVA with Tukey’s multiple comparisons test) (N). For C, E, G, I, K, and N, each data point indicates an individual mouse. Data are displayed as mean ± SEM.