Abstract
The anti-leukemia activity of NK cells helps prevent relapse during hematopoietic stem cell transplantation (HSCT) in leukemia patients. However, the factors that determine the sensitivity or resistance of leukemia cells in the context of NK-mediated cytotoxicity are not well-established. Here, we performed a genome-wide CRISPR screen in the human chronic-myelogenous-leukemia (CML) cell line K562 to identify genes that regulate the vulnerability of leukemia cells to killing by primary human NK cells. The distribution of guide RNAs (gRNAs) in K562 cells that survived co-incubation with NK cells showed that loss of NCR3LG1, which encodes the ligand of the natural cytotoxicity receptor NKp30, protected K562 cells from killing. In contrast, loss of genes that regulate the antigen-presentation and interferon-γ-signaling pathways increased the vulnerability of K562 cells. The addition of IFN-γ neutralizing antibody increased the susceptibility of K562 cells to NK-mediated killing. Upregulation of MHC class I on K562 cells after co-incubation with NK cells was dependent on IFNGR2. Analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) showed that low IFNGR2 expression in cancer tissues was associated with improved overall survival in acute myeloid leukemia (AML) and Kidney Renal Clear Cell Carcinoma (KIRC) patients. Our results, showing that the upregulation of MHC class I by NK-derived IFN-γ leads to resistance to NK cytotoxicity, suggest that targeting IFN-γ responses might be a promising approach to enhance NK cell anti-cancer efficacy.
Highlights
NK cells are crucial for cancer immune surveillance due to their robust effector function and intrinsic anti-cancer activity
NK cells can be activated by cancer cells that have upregulated the expression of ligands for NK cell activating receptors and down-regulated MHC class I expression
We identified a potential negative regulation of anti-leukemia NK cell responses through MHC class I upregulation mediated by NK-derived IFN-γ, which might be targeted in cancer immunotherapy to enhance NK cell activity
Summary
NK cells are crucial for cancer immune surveillance due to their robust effector function and intrinsic anti-cancer activity. The responses of NK cells to cancer or infected cells are determined by the integration of signals from activating and inhibitory receptors [1]. Some cancer or stressed cells upregulate ligands for NK activating receptors, thereby stimulating NK cell responses. NK cells express a broad array of receptors to recognize ligands on cancer cells, activation signaling alone is not sufficient to determine NK cell responses. Signaling from inhibitory receptors locally blocks activation signaling and prevents NK cell activation from the beginning. Engagement of these inhibitory receptors by their respective MHC class I ligands protects NK cells from chronic stimulation and maintains them in a highly responsive state, a process termed “education” or “licensing” [4]. NK cells can be activated by cancer cells that have upregulated the expression of ligands for NK cell activating receptors and down-regulated MHC class I expression
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