TY - JOUR
T1 - CD8+ T cells regulate bone tumor burden independent of osteoclast resorption
AU - Zhang, Kaihua
AU - Kim, Seokho
AU - Cremasco, Viviana
AU - Hirbe, Angela C.
AU - Novack, Deborah V.
AU - Weilbaecher, Katherine
AU - Faccio, Roberta
PY - 2011/7/15
Y1 - 2011/7/15
N2 - Blockade of osteoclast (OC) activity efficiently decreases tumor burden as well as associated bone erosion in immune-compromised animals bearing human osteolytic cancers. In this study, we showed that modulation of antitumor T-cell responses alters tumor growth in bone, regardless of OC status, by using genetic and pharmacologic models. PLCγ2-/- mice, with dysfunctional OCs and impaired dendritic cell (DC)-mediated T-cell activation, had increased bone tumor burden despite protection from bone loss. In contrast, Lyn-/- mice, with more numerous OCs and a hyperactive myeloid population leading to increased T-cell responses, had reduced tumor growth in bone despite enhanced osteolysis. The unexpected tumor/bone phenotype observed in PLCγ2-/- and Lyn-/- mice was transplantable, suggesting the involvement of an immune component. Consistent with this hypothesis, T-cell activation diminished skeletal metastasis whereas T-cell depletion enhanced it, even in the presence of zoledronic acid, a potent antiresorptive agent. Importantly, injection of antigen-specific wild-type cytotoxic CD8+ T cells in PLCγ2-/- mice or CD8 + T-cell depletion in Lyn-/- mice normalized tumor growth in bone. Our findings show the important contribution of CD8+ T cells in the regulation of bone metastases regardless of OC status, thus including T cells as critical regulators of tumor growth in bone.
AB - Blockade of osteoclast (OC) activity efficiently decreases tumor burden as well as associated bone erosion in immune-compromised animals bearing human osteolytic cancers. In this study, we showed that modulation of antitumor T-cell responses alters tumor growth in bone, regardless of OC status, by using genetic and pharmacologic models. PLCγ2-/- mice, with dysfunctional OCs and impaired dendritic cell (DC)-mediated T-cell activation, had increased bone tumor burden despite protection from bone loss. In contrast, Lyn-/- mice, with more numerous OCs and a hyperactive myeloid population leading to increased T-cell responses, had reduced tumor growth in bone despite enhanced osteolysis. The unexpected tumor/bone phenotype observed in PLCγ2-/- and Lyn-/- mice was transplantable, suggesting the involvement of an immune component. Consistent with this hypothesis, T-cell activation diminished skeletal metastasis whereas T-cell depletion enhanced it, even in the presence of zoledronic acid, a potent antiresorptive agent. Importantly, injection of antigen-specific wild-type cytotoxic CD8+ T cells in PLCγ2-/- mice or CD8 + T-cell depletion in Lyn-/- mice normalized tumor growth in bone. Our findings show the important contribution of CD8+ T cells in the regulation of bone metastases regardless of OC status, thus including T cells as critical regulators of tumor growth in bone.
UR - http://www.scopus.com/inward/record.url?scp=79960414809&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-3922
DO - 10.1158/0008-5472.CAN-10-3922
M3 - Article
C2 - 21602433
AN - SCOPUS:79960414809
SN - 0008-5472
VL - 71
SP - 4799
EP - 4808
JO - Cancer research
JF - Cancer research
IS - 14
ER -