UCLA

This is a novel report of the correlation and potential impact of the immune system, specifically NK cells and Interferon Gamma, in bone quality alteration related to pancreatic cancer in hu-BLT mice. For this purpose, we studied how MP2 tumors injected in hu-BLT mice affected the bone structure. Also, we analyzed how MP2 tumor-bearing mice injected with NK cells and fed with and without AJ2 influenced the bone structure.We demonstrated the suppression of NK cell cytotoxicity and decreased secretion of IFN‐γ in tumor‐bearing mice within all tissue compartments and restoration by super‐charged NK Cells. There was a remarkable correlation between the micro-CT analysis results, the induction and secretion of IFN‐γ, and bone morphology. The MP2 tumor-bearing mice injected with NK cells' cultures and fed with AJ2 presented increased bone formation with statistically significant higher trabecular bone volume compared to MP2 tumor-bearing mice group and MP2 tumor-bearing mice fed with AJ2 group, respectively. On the contrary, MP2 tumor-bearing mice showed decreased IFN‐γ and decreased bone formation. Consistent with the micro-CT findings, histological analysis of the AJ2 treatment group exhibited increased bone formation when compared to the Control and MP2 tumor groups. TRAP staining suggested more osteoclast activity and bone resorption in the MP2 tumor sample compared to the rest of the samples. Therefore, we can hypothesize that IFN‐γ induce secretion by NK cells, can inhibit tumor growth, and decreases skeletal complications of malignancy by directly acting on host cells to inhibits osteoclast formation and function. In our study, the enhanced osteolytic lesion formation in BLT tumor-bearing mice and NK cells' ability to secrete IFN‐γ to significantly reduce bone loss in tumor-bearing mice strongly supports a direct anti-osteoclastogenic role for IFN‐γ in the setting of cancer-induced bone disease. Furthermore, this report suggests that IFN‐γ can directly promote bone formation. Overall, our data demonstrated that the injection of NK cells into tumor‐bearing mice increased IFN‐γ secretion in hu-BLT mice. It also suggests that IFN‐γ has direct anti-tumor effects and potentially may suppress tumor-induced bone loss by directly targeting host osteoclasts to inhibit osteolysis. A better understanding of the bone marrow microenvironment and processes that influence tumor cell maintenance and bone growth should present opportunities to understand bone remodeling and osteolysis. To the best of our knowledge, the present work is a novel report of bone quality alteration related to pancreatic cancer in hu-BTL mice and the role of IFN‐γ secreted by NK cells in the suppression of tumor-induced bone loss and induction of bone formation.