The Resistance of Super Charged NK Cells to Immunosuppression in Tumor Microenvironment

We have previously demonstrated that natural killer (NK) cells are the primary immune effectors with the ability to mediate selection and differentiation of several different cancer stem cells/undifferentiated tumors via lysis and secreted or membrane-bound IFN-γ and TNF-α, respectively, leading to growth inhibition and curtailment of tumor metastasis. Here, we present an overview of our recent findings on the biology and significance of NK cells in the selection/differentiation of stem-like tumors using in vitro and in vivo studies conducted in the NSG and humanized-BLT mice. To establish the phenotypic and functional differences between primary NK and super-charged NK cells in vitro and in vivo, we analyzed their surface receptors, cytotoxicity, and cytokine secretion in either NK cells culture, NK-tumor co-culture, and CD34+ humanized mouse model condition. In in vitro studies, super-charged NK cells were more polyfunctional. They expressed higher surface receptors, performed higher cytotoxicity, and secreted higher IFN-γ compared to primary NK cells in vitro. When cultured with tumor tissues, super-charged NK cells were also more resistant to immunosuppression by the tumor tissues. Moreover, we observed similar inhibition of tumor growth by super-charged NK cells in the NSG-CD34+ humanized mouse model as we saw in hu-BLT mice. Therefore, due to their indispensable role in targeting cancer stem-like/undifferentiated tumors and various other vital functions of NK cells which are presented in this thesis, NK cells should be placed high in the armamentarium of tumor immunotherapy