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New Insights Into the Role of T cells in the Vicious Cycle of Bone Metastases [Metabolic Bone Disease]

Authors: Pierrick GJ Fournier ; John M Chirgwin ; Theresa A Guise, MDFaculty and Disclosures


Abstract and Introduction


Purpose of Review: Bone metastases interact with the bone microenvironment. Cancer cells modulate the functions of osteoblasts and osteoclasts to induce new bone formation or bone resorption, leading to secondary stimulation of tumor development. Recent findings suggest the involvement of T cells in this process.
Recent Findings: Bone metastatic cancer cells produce factors such as parathyroid hormone-related protein, interleukin-7, and interleukin-8 that can recruit or activate T cells. T cells are involved in bone remodeling and can induce osteoclastic resorption. Bone resorption releases transforming growth factor-β, however, which could suppress T-cell antitumor immune responses. Bisphosphonate antiresorptive drugs are the approved treatment for solid tumor bone metastases. They have recently been found to activate the cytolytic activity of γδ T cells. Thus, inhibitors of transforming growth factor-β or antiresorptive therapies may be effective enhancers of antitumor immune responses in bone.
Summary: T cells at the site of bone metastases may be functionally suppressed by factors in the bone microenvironment. Instead of acting against tumor cells, they may increase bone resorption, making bone a privileged site for tumor growth.


Breast, prostate, and lung cancers often cause bone metastases, which disrupt normal bone remodeling. They cause either new bone formation (osteoblastic response) or bone destruction (osteolytic response), which are associated with hypercalcemia, pain, fractures, and nerve compression syndromes.[1]

Cancer cells secrete products such as endothelin-1, which stimulate osteoblast proliferation.[2] Immature osteoblasts respond also to osteolytic factors, such as the parathyroid hormone-related protein (PTHrP), interleukin (IL)-1, IL-6, IL-8, and IL-11.[3] Most of these factors alter the expression of the regulatory molecules RANKL (receptor activator of nuclear factor-κB ligand) and osteoprotegerin to favor osteoclast formation and activation. Bone remodeling releases growth factors from the bone matrix during the osteoclastic bone resorption.[1] These cellular interactions drive a vicious cycle whereby tumor proliferation and bone destruction sustain each other. The bone microenvironment is thus a unique location for tumor growth and survival.

The involvement in bone metastases of cells in addition to osteoblasts and osteoclasts has been little studied. T lymphocytes, or T cells, actors of the immune system, can regulate bone remodeling. In this review, we focus on recent studies suggesting that T cells home to cancer cells in bone and contribute to the vicious cycle.

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