Abstract
Background and Aims: We have previously demonstrated that the stage of differentiation of tumors has profound effect on the function of NK cells, and that stem-like/poorly differentiated tumors were preferentially targeted by the NK cells. Therefore, in this study we determined the role of super-charged NK cells in immune mobilization, lysis, and differentiation of stem-like/undifferentiated tumors implanted in the pancreas of humanized-BLT (hu-BLT) mice fed with or without AJ2 probiotics. The phenotype, growth rate and metastatic potential of pancreatic tumors differentiated by the NK cells (NK-differentiated) or patient derived differentiated or stem-like/undifferentiated pancreatic tumors were investigated. Methods: Pancreatic tumor implantation was performed in NSG and hu-BLT mice. Stage of differentiation of tumors was determined using our published criteria for well-differentiated tumors exhibiting higher surface expression of MHC- class I, CD54, and PD-L1 (B7H1) and lower expression of CD44 receptors. The inverse was seen for poorly-differentiated tumors. Results: Stem-like/undifferentiated pancreatic tumors grew rapidly and formed large tumors and exhibited lower expression of above-mentioned differentiation antigens in the pancreas of NSG and hu-BLT mice. Unlike stem-like/undifferentiated tumors, NK-differentiated MP2 (MiaPaCa-2) tumors or patient-derived differentiated tumors were not able to grow or grew smaller tumors, and were unable to metastasize in NSG or hu-BLT mice, and they were susceptible to chemotherapeutic drugs. Stem-like/undifferentiated pancreatic tumors implanted in the pancreas of hu-BLT mice and injected with super-charged NK cells formed much smaller tumors, proliferated less, and exhibited differentiated phenotype. When differentiation of stem-like tumors by the NK cells was prevented by the addition of antibodies to IFN-γ and TNF-α, tumors grew rapidly and metastasized, and they remained resistant to chemotherapeutic drugs. Greater numbers of immune cells infiltrated the tumors of NK-injected and AJ2-probiotic bacteria-fed mice. Moreover, increased IFN-γ secretion in the presence of decreased IL-6 was seen in tumors resected and cultured from NK-injected and AJ2 fed mice. Tumor-induced decreases in NK cytotoxicity and IFN-γ secretion were restored/increased within PBMCs, spleen, and bone marrow when mice received NK cells and were fed with AJ2. Conclusion: NK cells prevent growth of pancreatic tumors through lysis and differentiation, thereby curtailing the growth and metastatic potential of stem-like/undifferentiated-tumors.
Highlights
Despite improvements in the therapeutic strategies, the five-year survival rate for pancreatic cancer patients remains dismal at 5%, with limited effectiveness of chemotherapeutic drugs in targeting these tumors [1,2,3]
Six different pancreatic tumor cell lines each characterized at poorly, intermediate, and well differentiated stages pathologically by other laboratories previously [45] were used to determine phenotype, susceptibility to NK cell-mediated cytotoxicity and secretion of IFN-γ directly correlating with the differentiation stages of the tumors
The growth potential of MP2 tumors in in vitro cultures is found to be 10–15 fold, whereas those of the NK-differentiated counterparts are between 1.5–4 fold when the same numbers of tumors are cultured within the same time period [27,49,51], and no or slight cell death could be seen in the cultures of either undifferentiated MP2 tumors or those differentiated by the NK cells [27]
Summary
Despite improvements in the therapeutic strategies, the five-year survival rate for pancreatic cancer patients remains dismal at 5%, with limited effectiveness of chemotherapeutic drugs in targeting these tumors [1,2,3]. It has previously been reported that decreased expression of MHC-class I is a hallmark of poorly differentiated tumors [10,11]. Low MHC-class I expression might favor survival of CSCs and explain the limited effectiveness of T-cell based immunotherapies in cancer patients [12,13]. We have previously demonstrated that the stage of differentiation of tumors has profound effect on the function of NK cells, and that stem-like/poorly differentiated tumors were preferentially targeted by the NK cells. In this study we determined the role of super-charged NK cells in immune mobilization, lysis, and differentiation of stem-like/undifferentiated tumors implanted in the pancreas of humanized-BLT (hu-BLT) mice fed with or without AJ2 probiotics. Results: Stem-like/undifferentiated pancreatic tumors grew rapidly and formed large tumors and exhibited lower expression of above-mentioned differentiation antigens in the pancreas of NSG and hu-BLT mice.
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