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Antibody-Mediated Inhibition of MICA/B Shedding Promotes NK Cell-Driven Tumor Immunity

ABSTRACT: MICA and MICB (MICA/B) are expressed by many human cancers due to cellular stress and tag cells for elimination by cytotoxic lymphocytes through NKG2D receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA/B proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA/B by human cancer cells. These antibodies inhibited tumor growth in multiple fully immuno-competent mouse models and also reduced human melanoma metastases in a humanized mouse model. Anti-tumor immunity was mediated mainly by NK cells through activation of NKG2D and CD16 Fc receptors. This novel approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.

OTHER RELATED OMICS DATASETS IN: PRJNA431361

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE109542 | GEO | 2018/02/01

REPOSITORIES: GEO

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Vaccine Induces Dual T cell plus NK cell Attack against Resistant Tumors

Project description:Here we report a cancer vaccine that induced a coordinated attack by diverse T cell and NK cell populations. The vaccine targeted the MICA and MICB (MICA/B) stress proteins expressed by many human cancers due to DNA damage. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumors evade immune recognition by proteolytic MICA/B cleavage. Vaccine-induced antibodies increased the density of MICA/B proteins on the surface of tumor cells by inhibiting proteolytic shedding, increased presentation of tumor antigens by dendritic cells to T cells, and enhanced the cytotoxic function of NK cells. Importantly, this vaccine maintained efficacy against MHC-I deficient tumors resistant to cytotoxic T cells through the coordinated action of NK cells and CD4 T cells. The vaccine was also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumors inhibited the later outgrowth of metastases. This vaccine design enables protective immunity even against tumors with common escape mutations.

2022-03-25 | GSE181997 | GEO

Bulk RNAseq of A375 cells treated with Panobinostat

Project description:The MICA and MICB genes are epigenetically regulated by HDACs. We tested if panobinostat, a broad spectrum HDAC inhibitor, affects the expression of MICA and MICB gene by a human melanoma cell line.

2020-02-19 | GSE145447 | GEO

MUC1-C IS A MASTER REGULATOR OF MICA/B NKG2D LIGAND AND EXOSOME SECRETION IN HUMAN CANCER CELLS

Project description:MUC1-C regulates expression of MICA/B NKG2D LIGAND AND enhance EXOSOME SECRETION IN HUMAN CANCER CELLS

2022-10-17 | GSE215308 | GEO

Reduced Proteolytic Shedding of Receptor Tyrosine Kinases is a Post-Translational Mechanism of Kinase Inhibitor Resistance.

Project description:Expression data from MDA-MB231 human breast cancer cells treated with metalloproteinase inhibitor (10uM BB94), MEK inhibitor (3uM PD325901), or DMSO control shows substantial overlap in the transcriptional responses arising from MEK and protease inhibition, suggesting a shared mechanism of action. Kinase inhibitor resistance often involves upregulation of poorly understood “bypass” signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTKs) including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of melanoma patients treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured non-invasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.

2016-03-21 | GSE77868 | GEO

Wool shedding

Project description:Study of natural wool shedding

| PRJEB31930 | ENA

Antibody-Mediated Inhibition of MICA/B Shedding Promotes NK Cell-Driven Tumor Immunity

Project description:Antibody-Mediated Inhibition of MICA/B Shedding Promotes NK Cell-Driven Tumor Immunity

| PRJNA431361 | ENA

A Landscape of Ectodomain Shedding by Quantitative Protein Terminomics

Project description:Ectodomain shedding is a proteolytic process that regulates level and function of membrane proteins. By quantitative protein terminomics consisting of N- and C-terminal peptide enrichment, TMT-labeling and mass spectrometry, we quantified protein termini in the cultured media across 10 human cell lines and identified cleavage sites on membrane proteins downregulated upon broad-spectrum metalloprotease inhibitor treatment.

2021-03-05 | PXD021378 | JPOST Repository

Multiple proteases are involved in mesothelin shedding by cancer cells

Project description:Mesothelin (MSLN) is a lineage restricted cell surface protein expressed in about 30% of human cancers and high MSLN expression is associated with poor survival in several different cancers1-4. The restricted expression of MSLN in normal tissue and its frequent expression in cancers make MSLN an excellent target for antibody-based therapies. Many clinical trials with agents targeting MSLN have been carried out but to date none of these agents have produced enough responses to obtain FDA approval4. MSLN shedding is an important factor that may contribute to the failure of these therapies, because shed MSLN acts as a decoy receptor and allows release of antibodies bound to cell-surface MSLN5,6. We have investigated the mechanism of shedding and show here that members of the ADAM, MMP and BACE families of proteases all participate in shedding, that more than one protease can produce shedding in the same cell, and that inhibition of shedding greatly enhances killing of cells by an immunotoxin targeting MSLN. Our data indicates that controlling MSLN shedding could greatly increase the activity of therapies that target MSLN.

2020-08-14 | MSV000085950 | MassIVE

Peripheral blood transcriptome responses to Salmonella Typhimurium in pigs differing in Salmonella shedding phenotypes

Project description:Salmonella species infect many vertebrate species, and pigs colonized with Salmonella enterica serovar Typhimurium (ST) are usually asymptomatic, making detection of these Salmonella-carrier pigs difficult. The variable fecal shedding of this gram-negative bacteria in such pigs is an important cause of foodborne illness and zoonotic disease. To investigate gene pathways and biomarkers associated with the variance in Salmonella shedding following experimental inoculation, we have initiated the first analysis of the whole blood transcriptional response induced by Salmonella. A population of pigs (n=40) was inoculated with ST and the peripheral blood and feces were collected between 2 and 20 days post-inoculation. Two groups of pigs with either low shedding (LS) or persistent shedding (PS) phenotypes were identified. The global transcriptional changes in response to ST inoculation were identified by Affymetrix Genechip?analysis of peripheral blood RNA at day 0 and day 2 post-inoculation. Forty pigs (n=40) was inoculated with ST. Four low shedding (LS) pigs and six persistent shedding (PS) pigs were identified. Transcriptom of peripheral blood collected at 0 and 2 dpi were identified by Affymetrix Genechip analysis.

2011-05-28 | E-GEOD-27000 | biostudies-arrayexpress

The pseudoprotease iRhom1 controls ectodomain shedding of membrane proteins in the nervous system

Project description:Proteolytic ectodomain shedding of membrane proteins is a fundamental mechanism to control the communication between cells and their environment. A key protease for membrane protein shedding is ADAM17, which requires a non-proteolytic subunit, either inactive Rhomboid 1 (iRhom1) or iRhom2 for its activity. While iRhom1 and iRhom2 are coexpressed in most tissues and appear to have largely redundant functions, the brain is an organ with predominant expression of iRhom1. Yet, little is known about the spatio-temporal expression of iRhom1 in mammalian brain and about its function in controlling membrane protein shedding in the nervous system. Here, we demonstrate that iRhom1 is expressed in mouse brain from the prenatal stage to adulthood with a peak in early postnatal development. In the adult mouse brain iRhom1 was widely expressed, including in cortex, hippocampus, olfactory bulb and cerebellum. Proteomic analysis of the secretome of primary neurons and of cerebrospinal fluid (CSF), obtained from iRhom1-deficient and control mice, identified several membrane proteins that require iRhom1 for their shedding in vitro or in vivo. One of these proteins was the ‘multiple-EGF-like-domains protein 10’ (MEGF10), a phagocytic receptor in the brain that is linked to the removal of amyloid and apoptotic neurons. MEGF10 was further validated as an ADAM17 substrate using ADAM17-deficient mouse embryonic fibroblasts. Taken together, this study discovers a role for iRhom1 in controlling membrane protein shedding in the mouse brain, establishes MEGF10 as an iRhom1-dependent ADAM17 substrate and demonstrates that iRhom1 is widely expressed in murine brain.

2021-10-07 | PXD028096 | Pride

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