Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation
Maya Kansara, Huei San Leong, Dan Mei Lin, Sophie Popkiss, Puiyi Pang, Dale W. Garsed, Carl R. Walkley, Carleen Cullinane, Jason Ellul, Nicole M. Haynes, Rod Hicks, Marieke L. Kuijjer, Anne-Marie Cleton-Jansen, Philip W. Hinds, Mark J. Smyth, David M. Thomas
Maya Kansara, Huei San Leong, Dan Mei Lin, Sophie Popkiss, Puiyi Pang, Dale W. Garsed, Carl R. Walkley, Carleen Cullinane, Jason Ellul, Nicole M. Haynes, Rod Hicks, Marieke L. Kuijjer, Anne-Marie Cleton-Jansen, Philip W. Hinds, Mark J. Smyth, David M. Thomas
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Research Article Oncology

Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation

Abstract

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.

Authors

Maya Kansara, Huei San Leong, Dan Mei Lin, Sophie Popkiss, Puiyi Pang, Dale W. Garsed, Carl R. Walkley, Carleen Cullinane, Jason Ellul, Nicole M. Haynes, Rod Hicks, Marieke L. Kuijjer, Anne-Marie Cleton-Jansen, Philip W. Hinds, Mark J. Smyth, David M. Thomas

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Figure 1

Rb1+/– mice are predisposed to the development of 45Ca-induced osteosarcomas compared with wild-type mice.

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Rb1+/– mice are predisposed to the development of 45Ca-induced osteosar...
(A) Radiation-induced (45Ca) mouse model of osteosarcoma. Mice at 28 days of age were injected with 1 μCi/g 45Ca intraperitoneally once weekly for 4 consecutive weeks and monitored for the growth of tumors. Mice develop tumors in the spine (70%) and limbs (18%), and then pelvis, cranium, scapula, and clavicle (12%), presumably reflecting distribution of isotope in vivo. (B) CT of tumors. (C and D) Micro-PET imaging using 18fluorine of tumors. (E) Example of gross bony morphology of osteosarcoma in tibiae. (F) Microscopic examination of mouse osteosarcoma. Sections were stained with hematoxylin and eosin. Arrows point to osteoids produced by the surrounding malignant osteoblastic cells (original magnification, ×100). Representative images are shown. (G) Cohorts of mice were injected with 45Ca and monitored for tumor onset. Kaplan-Meier plots of osteosarcoma onset (Rb1+/+ saline and Rb1+/+45Ca, n = 20; Rb1+/– saline, n = 22; Rb1+/–45Ca, n = 26). P = 0.005, Rb1+/+45Ca vs. Rb1+/–45Ca; P = 0.007, Rb1+/+ saline vs. Rb1+/+45Ca; P = 0.0004, Rb1+/– saline vs. Rb1+/–45Ca. (H) Kaplan-Meier plots of overall tumor onset, including osteosarcomas and pituitary and thyroid tumors (from Figure 1G). P = 0.03, Rb1+/+ saline vs. Rb1+/–45Ca; P = 0.02, Rb1+/– saline vs. Rb1+/–45Ca; P < 0.0001, Rb1+/+45Ca vs. Rb1+/–45Ca; P < 0.0001, Rb1+/+ saline vs. Rb1+/– saline, Mantel-Cox log-rank test.