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Bleomycin Exerts Ambivalent Antitumor Immune Effect by Triggering Both Immunogenic Cell Death and Proliferation of Regulatory T Cells

Bleomycin (BLM) is an anticancer drug currently used for the treatment of testis cancer and Hodgkin lymphoma. This drug triggers cancer cell death via its capacity to generate radical oxygen species (ROS). However, the putative contribution of anticancer immune responses to the efficacy of BLM has n...

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Autores principales: Bugaut, Hélène, Bruchard, Mélanie, Berger, Hélène, Derangère, Valentin, Odoul, Ludivine, Euvrard, Romain, Ladoire, Sylvain, Chalmin, Fanny, Végran, Frédérique, Rébé, Cédric, Apetoh, Lionel, Ghiringhelli, François, Mignot, Grégoire
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676388/
https://www.ncbi.nlm.nih.gov/pubmed/23762310
http://dx.doi.org/10.1371/journal.pone.0065181
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author Bugaut, Hélène
Bruchard, Mélanie
Berger, Hélène
Derangère, Valentin
Odoul, Ludivine
Euvrard, Romain
Ladoire, Sylvain
Chalmin, Fanny
Végran, Frédérique
Rébé, Cédric
Apetoh, Lionel
Ghiringhelli, François
Mignot, Grégoire
author_facet Bugaut, Hélène
Bruchard, Mélanie
Berger, Hélène
Derangère, Valentin
Odoul, Ludivine
Euvrard, Romain
Ladoire, Sylvain
Chalmin, Fanny
Végran, Frédérique
Rébé, Cédric
Apetoh, Lionel
Ghiringhelli, François
Mignot, Grégoire
author_sort Bugaut, Hélène
collection PubMed
description Bleomycin (BLM) is an anticancer drug currently used for the treatment of testis cancer and Hodgkin lymphoma. This drug triggers cancer cell death via its capacity to generate radical oxygen species (ROS). However, the putative contribution of anticancer immune responses to the efficacy of BLM has not been evaluated. We make here the observation that BLM induces immunogenic cell death. In particular, BLM is able to induce ROS-mediated reticulum stress and autophagy, which result in the surface exposure of chaperones, including calreticulin and ERp57, and liberation of HMBG1 and ATP. BLM induces anti-tumor immunity which relies on calreticulin, CD8(+) T cells and interferon-γ. We also find that, in addition to its capacity to trigger immunogenic cell death, BLM induces expansion of Foxp3+ regulatory T (Treg) cells via its capacity to induce transforming growth factor beta (TGFβ) secretion by tumor cells. Accordingly, Treg cells or TGFβ depletion dramatically potentiates the antitumor effect of BLM. We conclude that BLM induces both anti-tumor CD8(+) T cell response and a counteracting Treg proliferation. In the future, TGFβ or Treg inhibition during BLM treatment could greatly enhance BLM anti-tumor efficacy.
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spelling pubmed-36763882013-06-12 Bleomycin Exerts Ambivalent Antitumor Immune Effect by Triggering Both Immunogenic Cell Death and Proliferation of Regulatory T Cells Bugaut, Hélène Bruchard, Mélanie Berger, Hélène Derangère, Valentin Odoul, Ludivine Euvrard, Romain Ladoire, Sylvain Chalmin, Fanny Végran, Frédérique Rébé, Cédric Apetoh, Lionel Ghiringhelli, François Mignot, Grégoire PLoS One Research Article Bleomycin (BLM) is an anticancer drug currently used for the treatment of testis cancer and Hodgkin lymphoma. This drug triggers cancer cell death via its capacity to generate radical oxygen species (ROS). However, the putative contribution of anticancer immune responses to the efficacy of BLM has not been evaluated. We make here the observation that BLM induces immunogenic cell death. In particular, BLM is able to induce ROS-mediated reticulum stress and autophagy, which result in the surface exposure of chaperones, including calreticulin and ERp57, and liberation of HMBG1 and ATP. BLM induces anti-tumor immunity which relies on calreticulin, CD8(+) T cells and interferon-γ. We also find that, in addition to its capacity to trigger immunogenic cell death, BLM induces expansion of Foxp3+ regulatory T (Treg) cells via its capacity to induce transforming growth factor beta (TGFβ) secretion by tumor cells. Accordingly, Treg cells or TGFβ depletion dramatically potentiates the antitumor effect of BLM. We conclude that BLM induces both anti-tumor CD8(+) T cell response and a counteracting Treg proliferation. In the future, TGFβ or Treg inhibition during BLM treatment could greatly enhance BLM anti-tumor efficacy. Public Library of Science 2013-06-07 /pmc/articles/PMC3676388/ /pubmed/23762310 http://dx.doi.org/10.1371/journal.pone.0065181 Text en © 2013 Bugaut et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bugaut, Hélène
Bruchard, Mélanie
Berger, Hélène
Derangère, Valentin
Odoul, Ludivine
Euvrard, Romain
Ladoire, Sylvain
Chalmin, Fanny
Végran, Frédérique
Rébé, Cédric
Apetoh, Lionel
Ghiringhelli, François
Mignot, Grégoire
Bleomycin Exerts Ambivalent Antitumor Immune Effect by Triggering Both Immunogenic Cell Death and Proliferation of Regulatory T Cells
title Bleomycin Exerts Ambivalent Antitumor Immune Effect by Triggering Both Immunogenic Cell Death and Proliferation of Regulatory T Cells
title_full Bleomycin Exerts Ambivalent Antitumor Immune Effect by Triggering Both Immunogenic Cell Death and Proliferation of Regulatory T Cells
title_fullStr Bleomycin Exerts Ambivalent Antitumor Immune Effect by Triggering Both Immunogenic Cell Death and Proliferation of Regulatory T Cells
title_full_unstemmed Bleomycin Exerts Ambivalent Antitumor Immune Effect by Triggering Both Immunogenic Cell Death and Proliferation of Regulatory T Cells
title_short Bleomycin Exerts Ambivalent Antitumor Immune Effect by Triggering Both Immunogenic Cell Death and Proliferation of Regulatory T Cells
title_sort bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory t cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676388/
https://www.ncbi.nlm.nih.gov/pubmed/23762310
http://dx.doi.org/10.1371/journal.pone.0065181
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