The Uncovered Role of Immune Cells and NK Cells in the Regulation of Bone Metastasis

Bone is one of the main metastatic sites of solid tumors like breast, lung, and prostate cancer. Disseminated tumor cells (DTCs) and cancer stem cells (CSCs) represent the main target to counteract bone metastatization. These cells often localize in bone marrow (BM) at level of pre-metastatic niche: they can remain dormant for years or directly grow and create bone lesion, according to the different stimulations received in BM. The immune system in bone marrow is dampened and represents an appealing site for DTCs/CSCs. NK cells have an important role in controlling tumor progression, but their involvement in bone metastasis formation is an interesting and not fully investigated issue. Indeed, whether NK cells can interfere with CSC formation, kill them at the site of primary tumor, during circulation or in the pre-metastic niche needs to be elucidated. This review focuses on different aspects that regulate DTC/CSC life in bone and how NK cells potentially control bone metastasis formation

Denosumab and Zoledronic Acid differently affect circulating immune subsets: a possible role in the onset of MRONJ

This work investigated whether the anti-resorptive drugs (ARDs) zoledronic acid (Zol) and denosumab (Dmab) affect differently the levels of circulating immune cell subsets, possibly predicting the risk of developing medication-related ONJ (MRONJ) during the first 18 months of treatment. Blood samples were collected from 10 bone metastatic breast cancer patients receiving cyclin inhibitors at 0, 6, 12, and 18 months from the beginning of Dmab or Zol treatment. Eight breast cancer patients already diagnosed with MRONJ and treated with cyclin inhibitors and ARDs were in the control group. PBMCs were isolated; the trend of circulating immune subsets during the ARD treatment was monitored, and 12 pro-inflammatory cytokines were analyzed in sera using flow cytometry. In Dmab-treated patients, activated T cells were stable or increased, as were the levels of IL-12, TNF-α, GM-CSF, IL-5, and IL-10, sustaining them. In Zol-treated patients, CD8+T cells decreased, and the level of IFN-γ was undetectable. γδT cells were not altered in Dmab-treated patients, while they dramatically decreased in Zol-treated patients. In the MRONJ control group, Zol-ONJ patients showed a reduction in activated T cells and γδT cells compared to Dmab-ONJ patients. Dmab was less immunosuppressive than Zol, not affecting γδT cells and increasing activated T cells

Challenges of Periodontal Tissue Engineering: Increasing Biomimicry through 3D Printing and Controlled Dynamic Environment

In recent years, tissue engineering studies have proposed several approaches to regenerate periodontium based on the use of three-dimensional (3D) tissue scaffolds alone or in association with periodontal ligament stem cells (PDLSCs). The rapid evolution of bioprinting has sped up classic regenerative medicine, making the fabrication of multilayered scaffolds—which are essential in targeting the periodontal ligament (PDL)—conceivable. Physiological mechanical loading is fundamental to generate this complex anatomical structure ex vivo. Indeed, loading induces the correct orientation of the fibers forming the PDL and maintains tissue homeostasis, whereas overloading or a failure to adapt to mechanical load can be at least in part responsible for a wrong tissue regeneration using PDLSCs. This review provides a brief overview of the most recent achievements in periodontal tissue engineering, with a particular focus on the use of PDLSCs, which are the best choice for regenerating PDL as well as alveolar bone and cementum. Different scaffolds associated with various manufacturing methods and data derived from the application of different mechanical loading protocols have been analyzed, demonstrating that periodontal tissue engineering represents a proof of concept with high potential for innovative therapies in the near future

Evaluation of the immune state activation in patients affected by ONJ: preliminary data

Bisphosphonate (BP)-associated osteonecrosis of the jaw (ONJ) is a serious adverse event characterized by non-healing necrotic bone tissue of mandible or maxilla. BPs target osteoclasts, inhibiting their action and blocking bone resorption, nonetheless an increased bone resorption in the oral cavity is associated to ONJ. One of the causes of ONJ is the dysregulation of the immune system, in particular the strong reduction of gamma/delta T cells circulating in peripheral blood (PB). The rate of circulating osteoclast precursors (OCPs) is altered in bone metastatic patients, suggesting a systemic alteration of osteoclast compartment, but we do not know wether it is altered in cancer patients affected by active lesion of ONJ induced by Zoledronic acid treatment. By flow cytometric analysis of patients' and controls' PB cells, we studied the presence of different T cell subsets, according to the expression of gamma/delta chains, CD4, CD8, CD25 and CD69 and of OCPs. We also evaluated the capability of PBMCs to spontaneously differentiate into osteoclasts in vitro, which is an index of pathological bone resorption. Our preliminary results confirmed in ONJ patients a marked reduction in gamma/delta T cells compared to their level befor patients started BP treatment. The subsets of activated T cells and OCPs were not significantly modified. In ONJ patients, in vitro osteoclastogenesis was comparable to the one of healthy control, while before patients started BP treatment osteoclastogenesis was significantly increased. This result suggests that BPs correctly act in reducing the systemic activation of osteoclasts, associated to bone metastatic patients, as expected, but BPs fail to block osteoclast activity locally