Microenvironment and Immunology CD8þ T Cells Regulate Bone Tumor Burden Independent of Osteoclast Resorption

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. PLCg2 / 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 PLCg2 / 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 CD8þ T cells in PLCg2 / mice or CD8þ T-cell depletion in Lyn / mice normalized tumor growth in bone. Our findings show the important contribution of CD8þ T cells in the regulation of bone metastases regardless of OC status, thus including T cells as critical regulators of tumor growth in bone. Cancer Res; 71(14); 1–10. 2011 AACR.