title: The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy.
abstract: For the last four decades, the treatment of cancer has relied on four treatment modalities, namely surgery, radiotherapy, cytotoxic chemotherapy, and hormonotherapy. Most of these therapies are believed to directly attack and eradicate tumor cells. The emerging concept that cancer is not just a disease of a tissue or an organ but also a host disease relies on evidence of tumor-induced immunosuppression and polymorphisms in genes involved in host protection against tumors. This theory is now gaining new impetus, based on our recent data showing that optimal therapeutic effects require the immunoadjuvant effect of tumor cell death induced by cytotoxic anticancer agents. Here, we show that the release of the high mobility group box 1 protein (HMGB1) by dying tumor cells is mandatory to license host dendritic cells (DCs) to process and present tumor antigens. HMGB1 interacts with Toll-like receptor 4 (TLR4) on DCs, which are selectively involved in the cross-priming of anti-tumor T lymphocytes in vivo. A TLR4 polymorphism that affects the binding of HMGB1 to TLR4 predicts early relapse after anthracycline-based chemotherapy in breast cancer patients. This knowledge may be clinically exploited to predict the immunogenicity and hence the efficacy of chemotherapeutic regimens.
authors.affiliation: Institut Gustave Roussy (IGR), Villejuif, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Antoine
authors.initials: A
authors.lastname: Tesniere
authors.forename: Alfredo
authors.initials: A
authors.lastname: Criollo
authors.forename: Carla
authors.initials: C
authors.lastname: Ortiz
authors.forename: Rosette
authors.initials: R
authors.lastname: Lidereau
authors.forename: Christophe
authors.initials: C
authors.lastname: Mariette
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mira
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Thomas
authors.initials: T
authors.lastname: Tursz
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D003713:Dendritic Cells / Q000276:immunology; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000532:radiotherapy; D011110:Polymorphism, Genetic; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D024243:HMGB1 Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4