期刊
IMMUNITY
卷 53, 期 4, 页码 805-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2020.09.010
关键词
-
类别
资金
- BioBank Core Facility of the University Hospital Bonn, Germany
- Dr. Mildred Scheel Stiftung fuer Krebsforschung of the Deutsche Krebshilfe
- Melanoma Research Alliance Young Investigator grant [693786]
- Cancer Council Queensland project grant [1157048]
- Canadian Institutes of Health Research [MT-14429, MOP-82906, FDN-143338]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [GRK 2168]
- DFG [EXC2151-390873048]
- NHMRC
- Melanoma Institute Australia
- New South Wales Ministry of Health
- NSW Health Pathology
- Cancer Institute NSW
- Ainsworth Foundation
- University of Sydney Medical Foundation
- National Breast Cancer Foundation Australia [IIRS-18-159]
- NHMRC [APP1185907, 1132519, 1173958, 1138757, 1124690]
- Cancer Research Center of the University Hospital
- University of Zurich
- Swiss National Science Foundation [PP00P3_157448]
- National Health and Medical Research Council of Australia [1173958, 1138757, 1124690] Funding Source: NHMRC
The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes antitumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8(+) TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226(hi) TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226(+)CD8(+) T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.
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