Supercharged NK cells, unlike primary activated NK cells, effectively target ovarian cancer cells irrespective of MHC-class I expression

Abstract Ovarian cancers are the fifth leading cause of cancer-related death among women in the United States. Significant decreases in the numbers and function of NK-cells in patients, as shown in this paper may significantly contribute to the survival and expansion of aggressive poorly-differentiated-cancer-stem-like-cells (PDCSCs) with no/low expression of MHC-class I. Indeed, when gene set enrichment analysis (GSEA) was performed based on differentially expressed genes, decreased differentiation- and immune-related genes, and increased genes for cell cycle analysis were observed in recurrent tumors when compared to chemonaive ovarian tumors. We have previously identified and characterized a unique population of NK cells coined as supercharged NK cells (sNK) for their significant tumor killing capabilities. We demonstrate in this paper the increased gene expression as well as secretion of IFN-γ and TNF-α and increased avidity in binding to tumor cells by sNK cells. Unlike primary IL-2 activated NK cells, sNK cells greatly lysed OVCAR8 ovarian PDCSCs and well differentiated OVCAR4 tumors when assessed in a long-term killing assay using esight. Patient-derived ovarian cancer cells or patient derived xerografts (PDXs) with lower MHC class I expression, were highly susceptible to sNK cells, whereas well differentiated tumors with high expression of MHC class I were only susceptible to sNK cells when compared to primary IL-2 activated NK cells. Thus, the use of sNK cells in immunotherapy emerges as a potentially effective strategy to target and eliminate all clones of ovarian tumors, thereby preventing recurrences.