Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation.
Ionizing radiation (IR) and germline mutations in the retinoblastoma tumor suppressor gene (RB1) are the strongest risk factors for developing osteosarcoma. Recapitulating the human predisposition, we found that Rb1+/- mice exhibited accelerated development of IR-induced osteosarcoma, with a latency of 39 weeks. Initial exposure of osteoblasts to carcinogenic doses of IR in vitro and in vivo induced RB1-dependent senescence and the expression of a panel of proteins known as senescence-associated secretory phenotype (SASP), dominated by IL-6. RB1 expression closely correlated with that of the SASP cassette in human osteosarcomas, and low expression of both RB1 and the SASP genes was associated with poor prognosis. In vivo, IL-6 was required for IR-induced senescence, which elicited NKT cell infiltration and a host inflammatory response. Mice lacking IL-6 or NKT cells had accelerated development of IR-induced osteosarcomas. These data elucidate an important link between senescence, which is a cell-autonomous tumor suppressor response, and the activation of host-dependent cancer immunosurveillance. Our findings indicate that overcoming the immune response to senescence is a rate-limiting step in the formation of IR-induced osteosarcoma.
Maya
M
Kansara
Huei San
HS
Leong
Dan Mei
DM
Lin
Sophie
S
Popkiss
Puiyi
P
Pang
Dale W
DW
Garsed
Carl R
CR
Walkley
Carleen
C
Cullinane
Jason
J
Ellul
Nicole M
NM
Haynes
Rod
R
Hicks
Marieke L
ML
Kuijjer
Anne-Marie
AM
Cleton-Jansen
Philip W
PW
Hinds
Mark J
MJ
Smyth
David M
DM
Thomas
D000818:Animals; D001859:Bone Neoplasms / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002132:Calcium Radioisotopes / Q000633:toxicity; D016922:Cellular Senescence / Q000502:physiology*; D016207:Cytokines / Q000502:physiology; D016161:Genes, Retinoblastoma; D006801:Humans; D007157:Immunologic Surveillance; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D015850:Interleukin-6 / Q000172:deficiency / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009368:Neoplasm Transplantation / Q000276:immunology; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010006:Osteoblasts / Q000473:pathology; D012516:Osteosarcoma / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000502:physiology*
D002132:Calcium Radioisotopes; D016207:Cytokines; C508600:IL6 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein; C577686:interleukin-6, mouse