The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy.
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.
Apetoh
Lionel
L
Institut Gustave Roussy (IGR), Villejuif, France.
Ghiringhelli
François
F
Tesniere
Antoine
A
Criollo
Alfredo
A
Ortiz
Carla
C
Lidereau
Rosette
R
Mariette
Christophe
C
Chaput
Nathalie
N
Mira
Jean-Paul
JP
Delaloge
Suzette
S
André
Fabrice
F
Tursz
Thomas
T
Kroemer
Guido
G
Zitvogel
Laurence
L
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
D018943:Anthracyclines; D000970:Antineoplastic Agents; D024243:HMGB1 Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4