Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells

Hélène Bugaut; Mélanie Bruchard; Hélène Berger; Valentin Derangère; Ludivine Odoul; Romain Euvrard; Sylvain Ladoire; Fanny Chalmin; Frédérique Végran; Cédric Rébé; Lionel Apetoh; François Ghiringhelli; Grégoire Mignot

doi:10.1371/journal.pone.0065181

Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells

PLoS One. 2013 Jun 7;8(6):e65181. doi: 10.1371/journal.pone.0065181. Print 2013.

Authors

Hélène Bugaut¹, Mélanie Bruchard, Hélène Berger, Valentin Derangère, Ludivine Odoul, Romain Euvrard, Sylvain Ladoire, Fanny Chalmin, Frédérique Végran, Cédric Rébé, Lionel Apetoh, François Ghiringhelli, Grégoire Mignot

Affiliation

¹ INSERM, U866, Dijon, France.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Bleomycin / pharmacology*
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
Cell Death / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Female
Humans
Immunity / drug effects*
Immunity, Innate / drug effects
Mice
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / pathology*
Transforming Growth Factor beta / metabolism

Substances

Antineoplastic Agents
Transforming Growth Factor beta
Bleomycin

Grants and funding

This work was supported by special grants from the Fondation de France, the Association pour la Recherche sur le Cancer, the Institut National de la Santé et de la Recherche Médicale, the Ligue Contre le Cancer (Région Bourgogne), the Fondation pour la Recherche Médicale, and the Institut National du Cancer. GM was funded by the Association pour la Recherche sur le Cancer and FV by the Ligue Nationale contre le cancer. LA was supported by Agence Nationale pour la Recherche [ANR-10-PDOC-014-01]. HB is funded by École de l’Inserm Liliane Bettencourt. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.