UCLA

Natural Killer (NK) cells are essential components of the immune system, responsible for combating tumors and virulent pathogens. This thesis explores the effects of supercharged NK (sNK) cells, expanded through osteoclast co-culture, on uterine cancer cell lines and in vivo tumor models. The study focuses on comparing the cytotoxicity and functionality of sNK cells expanded using live and sonicated osteoclasts, investigating their effectiveness against poorly differentiated uterine cancer cell lines, and assessing their impact on tumor progression in humanized BLT (huBLT) mouse models.In Chapter 1, we establish the functional differences between sNK cells expanded through live and sonicated osteoclasts. Our results show that live osteoclast-expanded sNK cells exhibit superior cytotoxicity and higher IFN-γ secretion, indicating a more potent immune response. Chapter 2 investigates the cytotoxicity of sNK cells against the poorly differentiated AN3CA and well-differentiated HEC-1B uterine cancer cell lines. Our findings reveal that sNK cells exhibit higher cytotoxicity against AN3CA cells, comparable to their effect on stem-like cancer cells (OSCSC), while showing lower cytotoxicity against HEC-1B cells. Real-time cytotoxicity monitoring further supports these results, highlighting the dynamic and enhanced killing capability of sNK cells. Additionally, sNK cells demonstrate superior performance compared to primary NK (pNK) cells treated with IL-2 or IL-2+sAJ4, underscoring the enhanced efficacy of osteoclast-expanded sNK cells. In Chapter 3, we assess the in vivo efficacy of sNK cells in targeting AN3CA tumor progression in huBLT mice. The results indicate a significant reduction in tumor burden in sNK-treated mice, with decreased tumor weight and volume compared to controls. Furthermore, increased IFN-γ secretion levels in sNK-treated mice suggest a reinvigoration of the immune system's capacity to combat cancer, potentially reversing tumor-induced immunosuppression. Overall, this thesis demonstrates the enhanced cytotoxic capabilities and therapeutic potential of sNK cells in targeting poorly differentiated and aggressive cancer cells. The findings support the development of sNK cell-based immunotherapies as a promising approach for treating aggressive cancers and improving patient outcomes.