Open AccessA tumor-specific mechanism of Tregenrichment mediated by the integrin αvβ8
Author(s) -
Robert Seed,
Kenji Kobayashi,
Saburo Ito,
Naoki Takasaka,
Anthony Cormier,
Jillian M. Jespersen,
Jean Publicover,
Suprita Trilok,
Alexis J. Combes,
Nayvin W. Chew,
Jocelyne Chapman,
Matthew F. Krummel,
Jianlong Lou,
James D. Marks,
Yifan Cheng,
Jody L. Baron,
Stephen L. Nishimura
Publication year - 2021
Publication title -
science immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.83
H-Index - 51
ISSN - 2470-9468
DOI - 10.1126/sciimmunol.abf0558
Subject(s) - transforming growth factor , cancer research , in vivo , biology , integrin , in vitro , immune system , cell , mechanism (biology) , immunology , microbiology and biotechnology , biochemistry , philosophy , epistemology , genetics
Regulatory T cells (T regs ) that promote tumor immune evasion are enriched in certain tumors and correlate with poor prognosis. However, mechanisms for T reg enrichment remain incompletely understood. We described a mechanism for T reg 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 T reg differentiation in vitro. In vivo, tumor cell αvβ8 expression correlated with T reg enrichment, immunosuppressive T reg gene expression, and increased tumor growth, which was reduced in mice by αvβ8 inhibition or T reg 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 T reg enrichment.