转化生长因子
癌症研究
体内
整合素
细胞生物学
体外
细胞
免疫系统
机制(生物学)
免疫学
生物
化学
哲学
生物技术
认识论
生物化学
遗传学
作者
Robert Seed,Kenji Kobayashi,Saburo Ito,Naoki Takasaka,Anthony Cormier,Jillian M. Jespersen,Jean Publicover,Suprita Trilok,Alexis J. Combes,Nayvin W. Chew,Jocelyn S. Chapman,Matthew F. Krummel,Jianlong Lou,James G. Marks,Yifan Cheng,Jody L. Baron,Stephen L. Nishimura
出处
期刊:Science immunology
[American Association for the Advancement of Science (AAAS)]
日期:2021-03-26
卷期号:6 (57)
被引量:9
标识
DOI:10.1126/sciimmunol.abf0558
摘要
Regulatory T cells (Tregs) that promote tumor immune evasion are enriched in certain tumors and correlate with poor prognosis. However, mechanisms for Treg enrichment remain incompletely understood. We described a mechanism for Treg enrichment in mouse and human tumors mediated by the αvβ8 integrin. Tumor cell αvβ8 bound to latent transforming growth factor-β (L-TGF-β) presented on the surface of T cells, resulting in TGF-β activation and immunosuppressive Treg differentiation in vitro. In vivo, tumor cell αvβ8 expression correlated with Treg enrichment, immunosuppressive Treg gene expression, and increased tumor growth, which was reduced in mice by αvβ8 inhibition or Treg depletion. Structural modeling and cell-based studies suggested a highly geometrically constrained complex forming between αvβ8-expressing tumor cells and L-TGF-β-expressing T cells, facilitating TGF-β activation, independent of release and diffusion, and providing limited access to TGF-β inhibitors. These findings suggest a highly localized tumor-specific mechanism for Treg enrichment.
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