한빛사논문
- 조회385
Ha-Ram Park # 1, Anahita Shiva # 1, Portia Cummings 1, Seoyeon Kim 2, Sungsoo Kim 1, Eunhyeong Lee 1, Alessandra Leong 1, Subrata Chowdhury 1, Carrie Shawber 3, Richard Carvajal 4, Gavin Thurston 5, Joon-Yong An 2, Amanda W Lund 6, Hee Won Yang 1, Minah Kim 1
1Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York.
2School of Biosystems and Biomedical Sciences, College of Health Science, Korea University, Seoul, Korea.
3Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York.
4Department of Medicine, Columbia University Irving Medical Center, New York, New York.
5Regeneron Pharmaceuticals Inc., Tarrytown, New York.
6Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, NYU Langone Health, New York, New York.
#Contributed equally.
#H-R. Park and A. Shiva contributed equally to this article.
*Corresponding Author: Minah Kim
Abstract
T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ 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+ 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 immunotherapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ 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 signaling as a key mediator of T-cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma.
논문정보
- Research article
- 2023년 06월 (BRIC 등록일 2023-08-22)
- 국내+국외 연구진
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