Targeting Ewing sarcoma by ex vivo expanded IL1RAP CAR modified TGFbeta imprinted NK cells in combination with IL-15 agonist and anti-GD2 antibody
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ORGANISM(S): Mus musculus
PROVIDER: GSE310801 | GEO | 2026/07/15
REPOSITORIES: GEO
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Project description:IFN-g-induced gene expression profiles of UM-Chor1 cells were assessed by microarray analysis Chordoma is a rare bone tumor derived from notochord, which has shown to be resistant to conventional therapy, including chemotherapy and radiotherapy. Immunotherapy has the potential to be effective in cancers with resistance to conventional therapy. Checkpoint inhibition, including Programmed cell Death 1 (PD-1)/Programmed cell Death protein 1 (PD-L1) blockade has shown great promise in treating diverse cancers. The purpose of this study was to investigate the potential of anti-PD-L1 antibody therapy for chordoma. To this end, using 4 chordoma cell lines, we examined the expression of PD-L1 and performed in vitro NK cells killing assay for antibody-dependent cell-mediated cytotoxicity (ADCC) activity mediated by the anti-PD-L1 antibody, avelumab. Here, the expression of PD-L1 was markedly upregulated by IFN-g in all 4 chordoma cell lines, which resulted in increasing the sensitivity to ADCC. Next, to model a patient that received a tumor-antigen specific vaccine, chordoma cells were co-incubated with brachyury specific CD8+ T cells, culminating in significant upregulation of PD-L1 on the tumor cells mediated by CD8+ T cells IFN-g production. The functional consequence was the sensitivity of chordoma cells to ADCC mediated by avelumab. Finally, residential cancer stem cell subpopulations of chordoma cells were killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. Our findings show the potential of avelumab therapy in chordoma; a) alone, to enable endogenous NK cells to kill chordoma cells via ADCC, or b) in conjunction with T cells immunotherapy such a vaccine, to exploit enhanced NK cell killing of chordoma cells via ADCC.
2017-01-01 | GSE77732 | GEO
Project description:The paper describes a model of ADCC.
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This model is described in the article:
A mathematical model of antibody-dependent cellular cytotoxicity (ADCC)
F. Hoffman, D. Gavaghan, J. Osborne, I.P. Barrett, T. You, H. Ghadially, R. Sainson, R.W. Wilkinson, H.M. Byrne
Journal of Theoretical Biology 436 (2018) 39–50
Abstract:
Immunotherapies exploit the immune system to target and kill cancer cells, while sparing healthy tis- sue. Antibody therapies, an important class of immunotherapies, involve the binding to specific antigens on the surface of the tumour cells of antibodies that activate natural killer (NK) cells to kill the tu- mour cells. Preclinical assessment of molecules that may cause antibody-dependent cellular cytotoxicity (ADCC) involves co-culturing cancer cells, NK cells and antibody in vitro for several hours and measuring subsequent levels of tumour cell lysis. Here we develop a mathematical model of such an in vitro ADCC assay, formulated as a system of time-dependent ordinary differential equations and in which NK cells kill cancer cells at a rate which depends on the amount of antibody bound to each cancer cell. Numerical simulations generated using experimentally-based parameter estimates reveal that the system evolves on two timescales: a fast timescale on which antibodies bind to receptors on the surface of the tumour cells, and NK cells form complexes with the cancer cells, and a longer time-scale on which the NK cells kill the cancer cells. We construct approximate model solutions on each timescale, and show that they are in good agreement with numerical simulations of the full system. Our results show how the processes involved in ADCC change as the initial concentration of antibody and NK-cancer cell ratio are varied. We use these results to explain what information about the tumour cell kill rate can be extracted from the cytotoxicity assays.
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2024-09-02 | BIOMD0000000802 | BioModels
Project description:Challenges to developing immunotherapies for acute myeloid leukemia (AML) include the identification of suitable target antigens due to on-target-off-leukemia toxicity. CD70, expressed on AML bulk and leukemic stem cells with limited expression on healthy cells, has emerged as a promising target. This study evaluated CD70 as a target for NK-cell-based immunotherapy using a sugar-engineered antibody (SEA-CD70). Flow cytometry revealed CD70 expression ranging from 0.2% to 89.6% (median = 7.0%, n = 86) in primary AML cells across genetic subgroups; this expression remained stable at relapse (median = 3.9%, n = 14). SEA-CD70 showed potent, dose-dependent cytotoxicity against AML cell lines, primary cells and in an SCID mouse model, which correlated with CD70 expression levels. Notably, AML cells exposed to conditioned medium (CM) from activated T cells upregulated CD70. TNF-a was identified as the driver of CD70 upregulation, translating into enhanced antibody dependent cellular cytotoxicity (ADCC) against AML cells (cytotoxicity w/o TNF-a = 17.9% vs. with TNF-a = 34.3%, n = 13–15). Conversely, IFN-g exposure led to reduced ADCC (cytotoxicity w/o IFN-g = 17.9% vs. with IFN-g = 9.2%, n = 15), which is attributed to increased expression of NK inhibitory receptor ligands (HLA-ABC, HLA-E). Blocking of the corresponding inhibitory NK receptors (KIR/CD158b and NKG2A) partially reversed this effect. Similar findings were observed with a CD33-directed antibody, indicating a universal resistance mechanism against ADCC-based immunotherapy in AML. These findings suggest that IFN-g-dependent upregulation of HLA molecules contributes to resistance to NK-cell based therapy, warranting further biomarker studies from clinical trials.
2025-12-17 | GSE286349 | GEO
Project description:The immune responses to SARS-CoV-2 infection, especially neutralizing antibody generation, have been extensively studied. Beyond direct neutralization, antibodies can eliminate infected cells through engagement with natural killer (NK) cells. However, the molecular and cellular mechanisms by which NK cells collaborate with infection-induced antibodies in vivo during SARS-CoV-2 clearance remain elusive. Here, we analyzed a cohort of patients recovered from the initial SARS-CoV-2 infection to dissect the relationship between viral clearance and antibody-dependent cellular cytotoxicity (ADCC). We found that patients' plasma ADCC capacity was associated with a slower rate of viral clearance and the blood T follicular helper (Tfh) cluster. To elucidate the action of ADCC-inducing antibodies in SARS-CoV-2 infection, we isolated a monoclonal antibody (mAb) with strong ADCC activity. This ADCC-inducing mAb elicited a transcriptional program linked to viral RNA transcription and protein glycosylation. Furthermore, spatial transcriptomics analysis revealed enriched expression of several NK marker genes in discrete spots within the lungs of SARS-CoV-2-infected mice treated with the ADCC-inducing antibody. Consistently, human peripheral blood NK cells ligated with the ADCC-inducing antibody displayed evolutionarily conserved NK cell clusters, similar to those elicited in mice. Together, our study elucidates the temporally coherent action of specific NK cell subsets and ADCC-inducing antibodies in controlling SARS-CoV-2 infection.
2026-06-21 | GSE300023 | GEO
Project description:Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) induced by natural killer (NK) cells is one important mechanism by which cetuximab exerts its anti-tumoral effect. Therefore, molecular characterization of NK cells subpopulations may identify predictive biomarkers of cetuximab efficacy in mCRC patients and would provide novel therapeutic targets to enhance cetuximab-mediated ADCC.
2025-05-23 | PXD057989 | Pride
Project description:Pediatric patients with recurrent metastatic Ewing sarcoma (ES) have a dismal 5-year survival of < 30% largely secondary to treatment resistance in the tumor microenvironment (TME). Novel therapeutic approaches are desperately needed and represent an unmet need. Here, we developed a chimeric antigen receptor (CAR) expressing natural killer (NK) cell targeting melanoma cell adhesion molecule (MCAM) by electroporation of CAR mRNA into ex-vivo expanded NK cells. Expression of anti-MCAM CAR significantly and specifically enhanced NK cytotoxic activity compared to mock NK cells against MCAMhigh ES cells in vitro, and significantly reduced lung metastasis and extended animal survival in an orthotopic xenograft mouse model of ES. However, anti-MCAM CAR NK cells had minimal effects on decreasing primary tumor growth in vivo. We performed transcriptome profiling in patient-derived xenografts to identify the underlying mechanisms of NK cell resistance in ES TME.
2024-09-18 | GSE251936 | GEO
Project description:NK cells are an essential component for the control of influenza infection, acting to both clear virus-infected cells and release antiviral cytokines. Engagement of the NK cell CD16-receptor by antibody-coated influenza-infected cells results in antibody-dependent cellular cytotoxicity (ADCC). Though NK cell-mediated ADCC is an important mechanism to control influenza, influenza infection itself may act to enhance the potency of NK cell ADCC. To understand if virus-infected cells increase NK cell activation, we co-cultured human PBMCs with influenza-infected human alveolar epithelial (A549) cells and evaluated the capacity of NK cells to mediate ADCC. Pre-incubation of PBMCs with influenza-infected target cells markedly enhanced the functionality of NK cells by ADCC antibodies in response to HA immune-complexes containing intravenous immunoglobulin (IVIG), allogenic target cells, with and without rituximab. Trans-well and supernatant transfer experiments showed that virus released into the supernatant is responsible for the enhanced functionality of NK cells, which is apparent at both the protein and RNA transcriptomic levels. Furthermore, cytokine multiplex data, RNA sequencing and cytokine blocking/supplementation experiments showed Type I interferons released from PBMCs were the primary mechanism of the influenza-induced increased NK cell functionality and ADCC potency. Importantly, the influenza infection-mediated increase in NK cell mediated anti-influenza ADCC was mimicked by the type I interferon agonist Poly-IC. This suggests a potential mechanism for enhancing monoclonal antibody therapies for influenza. We conclude that influenza-infection induced secretion of type I interferons enhances the ADCC capacity of NK cells and this pathway may potentially be manipulated to improve anti-influenza therapies.
2019-01-03 | GSE115203 | GEO
Project description:Antibody dependent cell-mediated cytotoxicity (ADCC) provides a model for uncovering immune resistance mechanisms. We continuously exposed epidermal growth factor receptor (EGFR)+ A431 cells to KIR-deficient NK92-CD16V effector cells and the anti-EGFR mAb cetuximab. Persistent ADCC exposure yielded ADCC-resistant cells (ADCCR1) that, compared with control ADCC-sensitive cells (ADCCS1), exhibited reduced EGFR expression, overexpression of histone- and interferon-related genes and failure to activate NK cells, without evidence of epithelial: mesenchymal transition. These properties gradually reversed following withdrawal of ADCC selection pressure. A second A431-derived ADCC-resistant cell line maintained EGFR expression. Remarkably, ADCCR1 cells possessed lower expression of multiple cell surface molecules that contribute to cell: cell interactions and immune synapse formation. Classic immune checkpoints did not modulate ADCC in this unique model system of immune resistance. Just as giant tortoises (Testudinidae) can hide in their shells to avoid predation, this novel immune evasion mechanism, termed testudinidosis, can protect cells against immune attack.
2021-05-16 | GSE114545 | GEO
Project description:INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to chemotherapy and immunotherapy due to a tumor microenvironment (TME) dominated by myeloid-stromal immunosuppressive circuitries and T-cell dysfunction. Key mediators of this chemoimmunoresistance are interleukin-1 (IL-1) family cytokines (IL-1α/β, IL-33, IL-36), which converge on IL-1 receptor accessory protein (IL1RAP) signaling to reinforce a tolerogenic, pro-inflammatory TME. We hypothesized that IL1RAP-expressing myeloid-stromal compartments sustain a therapeutic barrier in PDAC, and that disrupting this via pharmacologic IL1RAP inhibition could reprogram the TME to enhance chemoimmunotherapy efficacy. METHODS: Chemoresistance in PDAC samples from Human Tumor Atlas Network (HTAN) was stratified by cell-type IL1RAP expression. Clinical outcomes in patients treated with anti-IL1RAP Ab nadunolimab (Nadu)+gemcitabine+nab-paclitaxel (GnP) in Phase II CANFOUR trial (NCT03267316) were stratified by immune and stromal IL1RAP expression; paired PDAC biopsies pre-/post-treatment were analyzed by mIF. Preclinical studies were conducted in the IL1RAPhi stromatogenic Ptf1aCre/+;LSL-KrasG12D;Tgfbr2fl/fl (PKT) murine model. Nadu surrogate Ab-treated tumors were analyzed by scRNAseq, flow cytometry, and histology. Combination Nadu, GnP, and anti-PD1 therapy was tested in survival \ studies. RESULTS: In HTAN dataset, IL1RAP expression was elevated across multiple TME compartments—myeloid, cancer-associated fibroblast (CAF), and tumor cells; notably, IL1RAP was selectively enriched in chemotherapy-resistant (vs sensitive) samples, predominantly in myeloid and CAF/stromal transcriptomes. Stratification of evaluable specimens from CANFOUR trial revealed correlation between high stromal/CAF (p=0.0058) and myeloid (p=0.014) IL1RAP expression and prolonged duration of response to Nadu+GnP. In PKT mice, Nadu treatment reduced tumor volume (p=0.019) and stromal fibrosis. Flow cytometry showed reduced trafficking/persistence (p=0.0077) and increased T-cell abundance (p=0.0033), which were corroborated by mIF in paired human PDAC biopsies pre/post Nadu treatment, showing diminished CD11b+CD14+/CD15+ myeloid infiltration and expansion of GzmB+Ki67+CD8+ T-cells. scRNAseq in PKT tumors revealed reprogramming in myeloid (↑antigen presentation and Type IIFN response; ↓IL-1/TNF signaling) and T-cell (↑activation/memory, TCR engagement, IL-2 signatures; ↓regulatory/exhausted states) subsets. Phenotypic skewing toward memory progenitor-exhausted CD8+ subsets (Ly108+CD69+/-) supported enhanced immune responsiveness. Triple therapy with Nadu, GnP, and anti-PD-1 significantly prolonged survival versus controls (p<0.001). CONCLUSIONS: IL1RAP-expressing myeloid-stromal networks may represent a distinct therapeutic barrier in PDAC, which can be disrupted pharmacologically to invigorate immunotherapy-permissive CD8+ T-cell subsets and improve chemoimmunotherapy sensitivity. These findings support an upcoming neoadjuvant trial combining nadunolimab with chemoimmunotherapy in patients with operable PDAC.
2026-04-27 | GSE310710 | GEO
Project description:Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations. Methods: We examined if olaparib, when combined with IgG1 antibody-dependent cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAbs) cetuximab (anti-EGFR), or avelumab (anti-PD-L1), would increase tumor cell sensitivity to killing by natural killer (NK) cells independently of BRCA status or mAb target upregulation. BRCA mutant and BRCA wildtype (WT) prostate carcinoma cell lines were pretreated with olaparib and then exposed to NK cells in the presence or absence of cetuximab or avelumab. Results: NK-mediated killing was significantly increased in both cell lines and was further increased using the ADCC-mediating mAbs. Pre-exposure of NK cells to recombinant IL-15/IL-15RA further increased the lysis of olaparib treated tumor cells. In addition, olaparib treated tumor cells were killed to a significantly greater degree by engineered high-affinity NK cells (haNK). We show here for the first time that (a) olaparib significantly increased tumor cell sensitivity to NK killing and ADCC in both BRCA WT and BRCA mutant prostate carcinoma cells, independent of PD-L1 or EGFR modulation; (b) mechanistically, treatment with olaparib upregulated death receptor TRAIL-R2, and (c) olaparib significantly enhanced NK killing of additional tumor types, including breast, non-small cell lung carcinoma, and chordoma. Conclusions: These studies support the combined use of NK- and ADCC-mediating agents with correctly timed PARP inhibition.
2018-12-11 | GSE121682 | GEO