A tumor-specific mechanism of T _reg enrichment mediated by the integrin αvβ8

Abstract

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.

Inflammatory response-based subtyping and potential therapeutic strategies for triple-negative breast cancer

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Clinical adoptive regulatory T Cell therapy: State of the art, challenges, and prospective

“…Dendritic cells continually present self and non-self- antigens, thereby promote tolerance via control of Tregs. Integrin αvβ8 on dendritic cells can activate TGF-β, a process that can contribute to the development of pTregs, especially in tumours ( Seed et al, 2021 ). Disruption of dendritic cell-expressed TGFβ receptor (TGFβR) impairs the tolerogenic function of dendritic cells and fosters autoimmunity ( Ramalingam et al, 2012 ).…”

Perinatal derivatives: How to best validate their immunomodulatory functions

“…However, not all T lymphocytes mediate defense functions, a proportion of them, especially the regulatory T cells mediate tolerogenic functions that are required during the whole course of pregnancy and other developmental and regenerative processes ( Weirather et al, 2014 ; Boothby et al, 2020 ; Fung et al, 2020 ; Green et al, 2021 ). As important as these regulatory T cell functions are, regulatory T cells also promote tumor growth and have been identified as promising targets in anti-tumor therapies ( Paluskievicz et al, 2019 ; Bai et al, 2020 ; Seed et al, 2021 ).…”