Genome-scale screens identify factors regulating tumor cell responses to natural killer cells

Abstract

To systematically define molecular features in human tumour cells which determine their degree of sensitivity to human allogeneic natural killer (NK) cells, we quantified the NK cell responsiveness of hundreds of molecularly-annotated "DNA-barcoded" solid tumour cell lines in multiplexed format and applied genome-scale CRISPR-based gene editing screens in several solid tumour cell lines to functionally interrogate which genes in tumour cells regulate the response to NK cells. In these orthogonal studies, NK-sensitive tumour cells tend to exhibit "mesenchymal-like" transcriptional programs; high transcriptional signature for chromatin remodeling complexes; high levels of B7-H6 (NCR3LG1); low levels of HLA-E/antigen presentation genes. Importantly, transcriptional signatures of NK cell-sensitive tumour cells correlate with immune checkpoint inhibitor (ICI) resistance in clinical samples. This study provides a comprehensive map of mechanisms regulating tumour cell responses to NK cells, with implications for future biomarker-driven applications of NK cell immunotherapies.

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

“…Selinexor is currently being assessed in a clinical trial in combination with anti-CD20 antibodies for patients with advanced B cell non-Hodgkin lymphoma (NCT03147885) and HLA-E downregulation by selinexor may therefore contribute to ADCC in this setting. A recent study identified that HLA-E suppresses NK cell sensitivity to tumor cells and that resistance to immune checkpoint blockade therapy in multiple clinical studies correlates with an NK sensitivity gene signature, including HLA-E ( 51 ). This data indicates that therapies which can stimulate NK activation, for example by disruption of NKG2A:HLA-E interactions, may overcome immune checkpoint blockade resistance.…”

B7H6 Serves as a Negative Prognostic Marker and an Immune Modulator in Human Pancreatic Cancer

“…B7H6 interacts with NK cells through the surface receptor NKp30, and the interaction plays an important role in NK cellrelated immune responses (10). Sheffer et al found that knocking out B7H6 from the surface of colorectal adenocarcinoma decreased the cytotoxicity of primary NK cells (38). Downregulation of cell-surface B7H6 expression on tumor cells also impaired tumor recognition by NK cells, helping tumor cells escape from NK cell-mediated killing (39).…”

Natural killer cell division regulates FcεRIγ expression downstream of mTOR activity

“…Viral infections can lead to the accumulation of CD56 dim CD16 + NKG2A +/- NKG2C +/- FcRγ -/low NK cells, yet the molecular mechanisms regulating FcRγ levels are not well defined. As this adaptor protein regulates the function of NKp30, NKp46, and CD16, which are shown to take part in anti-viral responses, cancer immunosurveillance, and tumor rejection, it is important to better characterize the mechanism of FcRγ regulation 8 .…”

“…Human cytomegalovirus (HCMV) infection can lead to the expansion of a subset of mature CD56 dim CD16 + CD57 +/- FcRγ -/low NK cells that exhibit stable population frequencies over years 6,7 . Reduced FcRγ levels in mature CD56 dim CD16 + can be associated with lower surface NKp30 and NKp46 levels, which may lead to reduced NK cell responses against tumors expressing ligands for these activating receptors 8–11 , yet have a minor influence on CD16 expression in vivo 5 . Moreover, CD56 dim CD16 + FcRγ -/low NK cells exhibit a higher CD16-mediated response, possibly due to its exclusive association with the CD3ζ homodimer or the CD57 phenotype 4,12,13 .…”