title: Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells.
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.
authors.affiliation: INSERM, U866, Dijon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Bugaut
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bruchard
authors.forename: Hélène
authors.initials: H
authors.lastname: Berger
authors.forename: Valentin
authors.initials: V
authors.lastname: Derangère
authors.forename: Ludivine
authors.initials: L
authors.lastname: Odoul
authors.forename: Romain
authors.initials: R
authors.lastname: Euvrard
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.forename: Fanny
authors.initials: F
authors.lastname: Chalmin
authors.forename: Frédérique
authors.initials: F
authors.lastname: Végran
authors.forename: Cédric
authors.initials: C
authors.lastname: Rébé
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Grégoire
authors.initials: G
authors.lastname: Mignot
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta; D001761:Bleomycin