Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.
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.
Apetoh
Lionel
L
Institut Gustave Roussy (IGR), 39 rue Camille Desmoulins, F-94805 Villejuif, France.
Ghiringhelli
François
F
Tesniere
Antoine
A
Obeid
Michel
M
Ortiz
Carla
C
Criollo
Alfredo
A
Mignot
Grégoire
G
Maiuri
M Chiara
MC
Ullrich
Evelyn
E
Saulnier
Patrick
P
Yang
Huan
H
Amigorena
Sebastian
S
Ryffel
Bernard
B
Barrat
Franck J
FJ
Saftig
Paul
P
Levi
Francis
F
Lidereau
Rosette
R
Nogues
Catherine
C
Mira
Jean-Paul
JP
Chompret
Agnès
A
Joulin
Virginie
V
Clavel-Chapelon
Françoise
F
Bourhis
Jean
J
André
Fabrice
F
Delaloge
Suzette
S
Tursz
Thomas
T
Kroemer
Guido
G
Zitvogel
Laurence
L
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D012516:Osteosarcoma / Q000188:drug therapy; D011725:Pyridines / Q000627:therapeutic use; D051197:Toll-Like Receptor 4 / Q000276:immunology*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011725:Pyridines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C431073:oxiplatin