IFNγ has variable effects on expression of MHC Class I and ICAM-1 in pediatric cancers which alter sensitivity to NK cell mediated lysis

Abstract

Abstract Interferon-γ (IFNγ), a cytokine secreted by effector lymphocytes upon activation, is known to cause upregulation of MHC class I in tumor cells, which has been associated with natural killer (NK) cell inhibition. NK cells are very heterogeneous with respect to receptor expression and their function depends on an interplay between these inhibitory and activating signals. In order to optimize NK cell therapy, it is essential to identify the NK cells expressing the optimal combination of receptors for a given target. In this study we evaluated tumor cell lines from the Pediatric Preclinical Testing Program to determine the impact of IFNγ on their expression of NK cell activating and inhibitory ligands, death receptors, and adhesion molecules using mass cytometry, and their correlation with tumor lysis. We found that IFNγ treatment can significantly increase ICAM-1 and/or HLA-ABC levels together or independently. When HLA-ABC increases without concomitant ICAM-1 upregulation, this is associated with decreased lysis. Conversely, when ICAM-1 upregulation exceeds HLA-ABC upregulation this is associated with increased conjugate formation and better NK cell cytotoxic activity. This increase in cytotoxicity and conjugate formation is lost after blocking ICAM-1. Time-lapse imaging of the NK cell interaction with tumor cells shows that NK cells require less time to form stable contacts with IFNγ treated tumor cells when compared to untreated tumor cells. This suggests that IFNγ induced upregulation of ICAM-1 enhances NK cell cytotoxic activity by reducing the time required for NK cells to form stable contacts with their target.