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Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers
Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this stu...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2005
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213151/ https://www.ncbi.nlm.nih.gov/pubmed/15824085 http://dx.doi.org/10.1084/jem.20042028 |
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author | Bronte, Vincenzo Kasic, Tihana Gri, Giorgia Gallana, Keti Borsellino, Giovanna Marigo, Ilaria Battistini, Luca Iafrate, Massimo Prayer-Galetti, Tommaso Pagano, Francesco Viola, Antonella |
author_facet | Bronte, Vincenzo Kasic, Tihana Gri, Giorgia Gallana, Keti Borsellino, Giovanna Marigo, Ilaria Battistini, Luca Iafrate, Massimo Prayer-Galetti, Tommaso Pagano, Francesco Viola, Antonella |
author_sort | Bronte, Vincenzo |
collection | PubMed |
description | Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy. |
format | Text |
id | pubmed-2213151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2005 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-22131512008-03-11 Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers Bronte, Vincenzo Kasic, Tihana Gri, Giorgia Gallana, Keti Borsellino, Giovanna Marigo, Ilaria Battistini, Luca Iafrate, Massimo Prayer-Galetti, Tommaso Pagano, Francesco Viola, Antonella J Exp Med Article Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy. The Rockefeller University Press 2005-04-18 /pmc/articles/PMC2213151/ /pubmed/15824085 http://dx.doi.org/10.1084/jem.20042028 Text en Copyright © 2005, The Rockefeller University Press 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 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Bronte, Vincenzo Kasic, Tihana Gri, Giorgia Gallana, Keti Borsellino, Giovanna Marigo, Ilaria Battistini, Luca Iafrate, Massimo Prayer-Galetti, Tommaso Pagano, Francesco Viola, Antonella Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers |
title | Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers |
title_full | Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers |
title_fullStr | Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers |
title_full_unstemmed | Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers |
title_short | Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers |
title_sort | boosting antitumor responses of t lymphocytes infiltrating human prostate cancers |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213151/ https://www.ncbi.nlm.nih.gov/pubmed/15824085 http://dx.doi.org/10.1084/jem.20042028 |
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