Natural Killer Cell-Based Therapy Combined with Probiotic Bacteria Supplementation Plays a Crucial Role in Regulating Bone Restoration in Cancer, Highlighting the Significance of IFN-γ

This study uncovered a significant correlation between interferon-gamma (IFN-γ) secretion from immune cells and bone quality alterations in pancreatic cancer-bearing humanized-BLT (hu-BLT) mice. Reduced bone formation and IFN‐γ inhibition were observed in tumor mice versus those without tumors. When AJ2 probiotic bacteria were fed to MP2 pancreatic tumor-bearing mice, it increased bone integrity compared to tumor-bearing mice not fed with AJ2, correlating with increased BV/TV, Tb/Th, Tb/n, and decreased Tb/Sp. Most significantly, pancreatic tumor-bearing hu-BLT mice treated with a combination of supercharged NK cells (sNK) injections and AJ2 supplementation exhibited elevated levels of bone formation and volume, surpassing untreated or solely AJ2-fed tumor mice. Combination of sNK cell infusion and AJ2 feeding further augmented the levels of Tb/Th and Tb/n and decreased the level of Tb/Sp. We also have observed a great correlation between data obtained by micro-CT-generated 3D images, bone thickness and morphology, and secretion of IFN‐γ from various tissues of hu-BLT mice. Increased IFN‐γ secretion was evident in cell cultures of isolated single cells of pancreas, spleen, PBMCs, splenocyte-derived NK cells, and bone marrow of mice receiving combined treatment of sNK cells and AJ2 compared to untreated tumor-bearing mice. TRAP staining data highlighted heightened osteoclastic activity and bone resorption in untreated tumor mice compared to those receiving sNK cell injections and AJ2 feeding or AJ2 feeding alone. This research unveils new insights into cancer-related bone quality changes in hu-BLT mice, emphasizing the potential of immune cell-derived IFN‐γ in counteracting tumor-induced bone loss and fostering bone formation.