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Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy
Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer. Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression through...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804934/ https://www.ncbi.nlm.nih.gov/pubmed/24127486 http://dx.doi.org/10.1084/jem.20130762 |
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author | Bos, Paula D. Plitas, George Rudra, Dipayan Lee, Sue Y. Rudensky, Alexander Y. |
author_facet | Bos, Paula D. Plitas, George Rudra, Dipayan Lee, Sue Y. Rudensky, Alexander Y. |
author_sort | Bos, Paula D. |
collection | PubMed |
description | Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer. Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3(DTR) knockin mice. T reg cell ablation resulted in significant determent of primary and metastatic tumor progression. Importantly, short-term ablation of T reg cells in advanced spontaneous tumors led to extensive apoptotic tumor cell death. This anti-tumor activity was dependent on IFN-γ and CD4(+) T cells but not on NK or CD8(+) T cells. Combination of T reg cell ablation with CTLA-4 or PD-1/PD-L1 blockade did not affect tumor growth or improve the therapeutic effect attained by T reg cell ablation alone. However, T reg cell targeting jointly with tumor irradiation significantly reduced tumor burden and improved overall survival. Together, our results demonstrate a major tumor-promoting role of T reg cells in an autochthonous model of tumorigenesis, and they reveal the potential therapeutic value of combining transient T reg cell ablation with radiotherapy for the management of poorly immunogenic, aggressive malignancies. |
format | Online Article Text |
id | pubmed-3804934 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-38049342014-04-21 Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy Bos, Paula D. Plitas, George Rudra, Dipayan Lee, Sue Y. Rudensky, Alexander Y. J Exp Med Article Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer. Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3(DTR) knockin mice. T reg cell ablation resulted in significant determent of primary and metastatic tumor progression. Importantly, short-term ablation of T reg cells in advanced spontaneous tumors led to extensive apoptotic tumor cell death. This anti-tumor activity was dependent on IFN-γ and CD4(+) T cells but not on NK or CD8(+) T cells. Combination of T reg cell ablation with CTLA-4 or PD-1/PD-L1 blockade did not affect tumor growth or improve the therapeutic effect attained by T reg cell ablation alone. However, T reg cell targeting jointly with tumor irradiation significantly reduced tumor burden and improved overall survival. Together, our results demonstrate a major tumor-promoting role of T reg cells in an autochthonous model of tumorigenesis, and they reveal the potential therapeutic value of combining transient T reg cell ablation with radiotherapy for the management of poorly immunogenic, aggressive malignancies. The Rockefeller University Press 2013-10-21 /pmc/articles/PMC3804934/ /pubmed/24127486 http://dx.doi.org/10.1084/jem.20130762 Text en © 2013 Bos et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Bos, Paula D. Plitas, George Rudra, Dipayan Lee, Sue Y. Rudensky, Alexander Y. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy |
title | Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy |
title_full | Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy |
title_fullStr | Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy |
title_full_unstemmed | Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy |
title_short | Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy |
title_sort | transient regulatory t cell ablation deters oncogene-driven breast cancer and enhances radiotherapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804934/ https://www.ncbi.nlm.nih.gov/pubmed/24127486 http://dx.doi.org/10.1084/jem.20130762 |
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