Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin αVβ8
Open accessAbstract
Significance: Immunosuppression by regulatory T cells (Tregs) is essential for the maintenance of self-tolerance, but it is detrimental in cancer because Tregs inhibit antitumor immunity. Development of therapeutic tools to block Tregs in patients with cancer requires a precise understanding of how human Tregs suppress immune responses. We recently identified an important mechanism implicating release of the active form of TGF-β1, a potently immunosuppressive cytokine, from GARP/latent TGF-β1 complexes on the surface of human Tregs. Here we unravel the molecular process leading to this release. We identify integrin αVβ8 as indispensable for TGF-β1 activation from GARP/latent TGF-β1 complexes. We show that anti-β8 monoclonals block immunosuppression by human Tregs in vivo and could thus serve in cancer immunotherapy.
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Treg cells contribute to macrophage and neutrophil polarization towards a regenerative rather than inflammatory cell state.
“and contribute to macrophage and neutrophil polarization towards a regenerative rather than inflammatory cell state58,63,82,145,172,173,218,219.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [82]
Treg cells functionally repress the tumor-killing activity of CD8+ T cells through various activities, including TGF-β1 activation.
“These then functionally repress, through various activities, including TGF-β1 activation82,145, the tumor-killing activity of CD8+ T cells 58,63,82,145,218,219”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [82]
Antibodies against integrin β8, which is expressed on tumor cells, Treg cells and DCs, have anti-tumor activity as monotherapy in some syngeneic cancer models.
“Notably, antibodies against integrin β8, which is expressed on tumor cells, Treg cells and DCs, have anti-tumor activity as monotherapy in some syngeneic cancer models82,85,319.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [82]
GARP, in cooperation with integrin αvβ8, is required for TGF-β1 activation at the surface of Treg cells.
“Since GARP, in cooperation with integrin αvβ8, is required for TGF-β1 activation at the surface of Treg cells82,320”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [82]
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“For example, previous research found that αvβ8 integrin-expressing tumor cells can evade host immunity by upregulating TGFβ signaling in immune cells.(204) The engineered antibody against αvβ8 integrin can block the release of active TGFβ by cancer cells and promote the anti-tumor immune reaction in pre-clinical mice…”
ResultOvercoming TGFβ-mediated immune evasion in cancer
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- Authors
- Stockis, J., Liénart, S., Colau, D., Collignon, A., Nishimura, S. L., Sheppard, D., Coulie, P. G., & Lucas, S.
- Affiliations
- de Duve Institute (BE)
- Ludwig Cancer Research (BE)
- University of California, San Francisco (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-11-06
- Volume
- 114
- Issue
- 47
- Pages
- E10161-E10168
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5703296
- OpenAlex
- W2767915360
- Cited by
- 111
- References
- 50
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 6 · 2023: 12 · 2022: 15 · 2021: 17 · 2020: 14 · 2019: 16 · 2018: 12
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- Funders
- Pfizer
- European Commission (HORIZON2020)
- Fédération Wallonie-Bruxelles
- Walloon excellence in life sciences and biotechnology
- H2020 European Research Council (682818)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- regulatory T cells, TGF-β1 activation, integrin αvβ8, GARP, latent TGF-beta1, immunosuppression, xenogeneic graft-versus-host disease, RGD-binding integrins, antibody blocking, T cell tolerance
- MeSH terms
- Animals, Antibodies, Monoclonal, Cells, Cultured, Disease Models, Animal, Graft vs Host Disease, Humans, Immune Tolerance, Membrane Proteins, Neoplasms, Transplantation, Heterologous, Integrins, Mice, SCID, T-Lymphocytes, Regulatory, Mice, Transforming Growth Factor beta1
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