期刊
NATURE
卷 561, 期 7723, 页码 331-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-018-0499-y
关键词
-
资金
- SU2C-St. Baldrick's Pediatric Dream Team Translational Research Grant [SU2C-AACR-DT1113]
- Alex's Lemonade Stand
- NIH [T32HL092332, R01AI067946, T32GM08812, DK56338, CA125123, 1S10OD020151-01]
- CPRIT [RP150578]
- Dan L. Duncan CCC
- [P01-CA080124]
- [R35-CA197743]
- [K08-GM123261]
- [P50-CA165962]
- NATIONAL CANCER INSTITUTE [P01CA080124, P50CA165962, P30CA125123, R35CA197743] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL092332] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI067946] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK056338] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [K08GM123261] Funding Source: NIH RePORTER
Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM , which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据