Metastasis of Breast Cancer Cells Inhibits Tumor Growth and Prevents Bone Depletion of Plasmacytoid Dendritic Cells

Elevated levels of plasmacytoid dendritic cells (pDC) have been reported in breast cancer patients, but the significance remains undefined. Using three immunocompetent mouse models of breast cancer bone metastasis, we identified a key role for pDC in facilitating tumor growth through immunosuppression and aggressive osteolysis. Following infiltration of macrophages upon breast cancer dissemination, there was a steady increase in pDC within the bone, which resulted in a sustained Th2 response along with elevated levels of regulatory T cells and myeloid-derived suppressor cells. Subsequently, pDC and CD4 + T cells, producing osteolytic cytokines, increased with tumor burden, causing severe bone damage. Microcomputed tomography and histology analyses of bone showed destruction of femur and tibia. The therapeutic significance of this finding was confirmed by depletion of pDC, which resulted in decreased tumor burden and bone loss by activating tumor-specific cytolytic CD8 + T cells and decreasing suppressor cell populations. Thus, pDC depletion may offer a novel adjuvant strategy to therapeutically influence breast cancer bone metastasis. N early 80–90% of breast cancer patients with advanced disease have osteolytic disease, characterized by increased bone damage resulting from enhanced osteoclast activity (1). The presence of such bone lesions usually signifies serious morbidity and a grave prognosis, with severe pain, pathological fractures, nerve compression syndromes, and hypercal-cemia (2). Current therapies for bone metastasis in breast cancer patients are limited and are focused only on symptomatic management , limiting the progression of established disease (3). Although a significant amount of research has been carried out on understanding breast cancer bone metastasis, not much is known about the events leading to the bone metastasis. Hence, a better understanding of the molecular mechanisms involved in the formation and progression of bone metastases is needed. Dissemination of the primary tumor to the bone triggers the production of osteolytic cytokines and growth factors that result in osteoclast activation and the promotion of tumor growth and immune suppression in the bone microenvironment (4). Conversely, products of bone cells are critical for normal development of the hematopoietic and immune systems (4). In osteopenic conditions, such as osteoporosis, bone destruction results from enhanced os-teoclast activity with a concomitant decrease in osteoblast numbers , without a significant alteration in the immune system (5). But the osteolytic bone changes observed in bone metastasis are triggered by a coordinated interplay of bone-homing cancer cells, osteoclasts, and the immune cells in the bone marrow (BM) (6). Thus, elucidation …