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Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication
Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens....
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012291/ https://www.ncbi.nlm.nih.gov/pubmed/35230974 http://dx.doi.org/10.1172/JCI155148 |
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author | Horn, Lucas A. Chariou, Paul L. Gameiro, Sofia R. Qin, Haiyan Iida, Masafumi Fousek, Kristen Meyer, Thomas J. Cam, Margaret Flies, Dallas Langermann, Solomon Schlom, Jeffrey Palena, Claudia |
author_facet | Horn, Lucas A. Chariou, Paul L. Gameiro, Sofia R. Qin, Haiyan Iida, Masafumi Fousek, Kristen Meyer, Thomas J. Cam, Margaret Flies, Dallas Langermann, Solomon Schlom, Jeffrey Palena, Claudia |
author_sort | Horn, Lucas A. |
collection | PubMed |
description | Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β activation signatures and collagen-rich environments have both been associated with T cell exclusion and lack of responses to immunotherapy. Here, we describe the effect of targeting collagens that signal through the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8(+) T cells, and repolarized suppressive macrophage populations, resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy. |
format | Online Article Text |
id | pubmed-9012291 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-90122912022-04-18 Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication Horn, Lucas A. Chariou, Paul L. Gameiro, Sofia R. Qin, Haiyan Iida, Masafumi Fousek, Kristen Meyer, Thomas J. Cam, Margaret Flies, Dallas Langermann, Solomon Schlom, Jeffrey Palena, Claudia J Clin Invest Research Article Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β activation signatures and collagen-rich environments have both been associated with T cell exclusion and lack of responses to immunotherapy. Here, we describe the effect of targeting collagens that signal through the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8(+) T cells, and repolarized suppressive macrophage populations, resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy. American Society for Clinical Investigation 2022-04-15 2022-04-15 /pmc/articles/PMC9012291/ /pubmed/35230974 http://dx.doi.org/10.1172/JCI155148 Text en © 2022 Horn et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Horn, Lucas A. Chariou, Paul L. Gameiro, Sofia R. Qin, Haiyan Iida, Masafumi Fousek, Kristen Meyer, Thomas J. Cam, Margaret Flies, Dallas Langermann, Solomon Schlom, Jeffrey Palena, Claudia Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication |
title | Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication |
title_full | Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication |
title_fullStr | Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication |
title_full_unstemmed | Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication |
title_short | Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication |
title_sort | remodeling the tumor microenvironment via blockade of lair-1 and tgf-β signaling enables pd-l1–mediated tumor eradication |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012291/ https://www.ncbi.nlm.nih.gov/pubmed/35230974 http://dx.doi.org/10.1172/JCI155148 |
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