Research ArticleTUMOR IMMUNOLOGY

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

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Science Immunology  26 Mar 2021:
Vol. 6, Issue 57, eabf0558
DOI: 10.1126/sciimmunol.abf0558

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Enriching your intratumoral Tregs

Regulatory T cells (Tregs) are immunosuppressive and enriched in the tumor microenvironment (TME), which subsequently leads to the promotion of tumor growth. The mechanism behind Treg enrichment in the TME is not known. Here, Seed et al. demonstrated that integrin αvβ8 expression on tumor cells induced Treg differentiation intratumorally by binding to latent TGF-β on T cells, leading to TGF-β activation. Antibody blockade of αvβ8 depleted intratumoral Tregs and delayed tumor growth in murine tumor models. However, targeting of TGF-β with small-molecule inhibitors to block Treg formation was ineffective, as modeling of αvβ8/latent TGF-β interactions showed limited access to TGF-β. Thus, these data suggest that targeting αvβ8 expression on tumors with antibodies can inhibit Treg formation and subsequent tumor growth, providing a potential therapeutic option for cancer patients.

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.

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