Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.

Abstract

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.

• Authors: Lionel Apetoh, François Ghiringhelli, Antoine Tesniere, Michel Obeid, Carla Ortiz, Alfredo Criollo, Grégoire Mignot, M Chiara Maiuri, Evelyn Ullrich, Patrick Saulnier, Huan Yang, Sebastian Amigorena, Bernard Ryffel, Franck J Barrat, Paul Saftig, Francis Levi, Rosette Lidereau, Catherine Nogues, Jean-Paul Mira, Agnès Chompret, Virginie Joulin, Françoise Clavel-Chapelon, Jean Bourhis, Fabrice André, Suzette Delaloge, Thomas Tursz, Guido Kroemer, Laurence Zitvogel
• Journal: Nature medicine (Nat Med) Vol. 13 Issue 9 Pg. 1050-9 (Sep 2007) ISSN: 1078-8956 [Print] United States
• PMID: 17704786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Pyridines
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• oxiplatin

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Bone Neoplasms (drug therapy)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, radiotherapy)
• Disease Models, Animal
• Humans
• Mice
• Mice, Inbred BALB C
• Neoplasms (drug therapy, radiotherapy)
• Organoplatinum Compounds (therapeutic use)
• Osteosarcoma (drug therapy)
• Pyridines (therapeutic use)
• Toll-Like Receptor 4 (immunology)