Journal of Carcinogenesis & Mutagenesis

Abstract

Dedifferentiation of Epithelial Tumors Enhances Cytotoxicity, Survival and Expansion of Allogeneic CD8+ T Cells and Natural Killer Cells

Anahid Jewett, Hiromi Nakamura, Meiying Wang, Antonia Teruel, Avina Paranjpe and Marcela Romero

Our recent findings have suggested an important role for the conditioning of Natural Killer cell effector function by the cancer stem cells as well as healthy untransformed stem cells, stromal monocytes and fibroblasts in cellular differentiation and tissue regeneration. We have also reported that de-differentiation or reversion of tumor cells or healthy non-transformed cells to a less-differentiated stage activated cytotoxic function of NK cells. In this report we examined the function of allogeneic CD8+ T cell cytotoxic function against de-differentiated tumors to determine whether induction of cytotoxic function by de-differentiated tumors is unique to the function of NK cells or that the cytotoxic function of CD8+ T cells is similarly induced when cultured with NFκB knock down tumors. Here, we demonstrate that dedifferentiation of tumors by the inhibition of NFκB nuclear function sensitizes the tumors to allogeneic CD8+ T cell mediated cytotoxicity, and increased survival and proliferation of T cells. Moreover, increased secretion of IFN-γ and GM-CSF by CD8+ T cells was observed when these cells were co-incubated with NFκB knock down tumors. More importantly, the levels of IL-6 secretion were significantly reduced in the co-cultures of CD8+ T cells and NFκB knock down tumors when compared to those obtained from the co-cultures of CD8+ T cells with vector-alone transfected tumors. In addition, treatment of tumor transfectants with IFN-γ resulted in a decrease in the cytotoxicity and cytokine secretion by CD8+ T cells. However, the function of cytotoxic T cells remained significantly higher in the presence of IFN-γ treated NFκB knock down tumors when compared to either untreated or IFN- γ treated vector alone transfected tumors. Thus, these results indicated that inhibition of NFκB function in tumors activates both NK and CTL functions, suggesting a potential role for both innate and adaptive immune effectors in differentiation and regeneration of the tissues.