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IFN-gamma exposure of MOLM-13 cells enhances HLA gene expression

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286349 | GEO | 2025/12/17

REPOSITORIES: GEO

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Project description:The paper describes a model of ADCC. Created by COPASI 4.26 (Build 213) 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. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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IFN-gamma exposure of MOLM-13 cells enhances HLA gene expression

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