UCLA

Natural Killer cells (NK) cells are known to limit growth and expansion of cancer stem cells by direct cytotoxicity, providing key cytokines such as IFN-γ and TNF-α, which drive differentiation of stem-like/poorly differentiated cancer stem cells and through antibody-dependent cell cytotoxicity (ADCC). One of the important surface antigens on transformed cells is Major Histocompatibility Complex class I chain-related protein A and B (MICA/MICB). Induction of NK cell-mediated cytotoxicity resistance and differentiation in the stem cells correlate with the increased expression of CD54, B7H1, and MHCI, and MICA/MICB and antibodies specific to MICA/MICB increased NK cell-mediated ADCC against differentiated oral and pancreatic tumors, while the stem-like/poorly differentiated cancer stem cells were not targeted. This antibody also increased IFN-γ secretion by NK cells when cultured with differentiated oral tumors expressing MICA/MICB. This study also showed that Expanded NK cells target both undifferentiated and differentiated tumor cells while primary NK cells preferentially target undifferentiated/Stem-like population. In addition, it showed that the combination of IL-2 and antiCD16 treatment induces split anergy in primary NK cells but not in super-charged NK cells and Expanded NK cells were found to mediate lower levels of ADCC than primary NK cells. Knowing the key role of IFN-γ production in differentiation of oral and pancreatic cancer cells, then aimed to determine strategies to increase NK cell-mediated production of IFN-γ and we showed that AJ2 probiotic bacteria and fucoidan extracted from Mekabu could individually increase NK cells’ IFN-γ secretion ability. The combination of AJ2 probiotic bacteria and fucoidan extracted from Mekabu resulted in synergic secretion of IFN-γ by NK cells. In conclusion, differentiated and stem-like/ poorly differentiated oral and pancreatic tumors have different expression level of MICA/MICB and can be targeted differentially through ADCC. Primary and Expanded NK cells have very different characteristics and biological functions and all the diverse functions of different subsets of NK cells should be considered in NK cell- immunotherapeutic approaches.