Angiopoietin-2-Dependent Spatial Vascular Destabilization Promotes T-cell Exclusion and Limits in Melanoma

◥ T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8 thorn T-cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy, and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T-cell infiltration to the tumor core. The spatial regulation of ANGPT2 in whole tumor cross-sections was analyzed in conjunction with T-cell distribution, vascular integrity, and response to immunotherapy in syngeneic murine melanoma models. T-cell exclusion was associated with ANGPT2 upregulation and elevated vascular leakage at the periphery of human and murine melanomas. Both pharmacologic and genetic blockade of ANGPT2 promoted CD8 thorn T-cell infiltration into the tumor core, exerting antitumor effects. Importantly, the reversal of T-cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 immune checkpoint blockade therapy in immunogenic, therapy-responsive mouse melanomas, but it also rendered nonresponsive tumors susceptible to immuno-therapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8 thorn T-cell infiltration to the tumor core, coincided with spatial TIE2 signaling activation and increased vascular integrity at the tumor periphery where endothelial expression of adhesion molecules was reduced. These data highlight ANGPT2/TIE2 sig-naling as a key mediator of T-cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma.

Automated summary

The position of T-cells in the tumor microenvironment affects their ability to encounter the tumor and kill it. The vascular destabilizing factor ANGPT2 causes vascular integrity issues in the tumor periphery, leading to a lack of T-cell infiltration in the tumor core, which is associated with a poor response to immunotherapy.