TNF-α and IFN-γ differentially regulate AML cell susceptibility to CD70-antibody-mediated cytotoxicity
Monika Sponheimer1,2, Kieron White1,2, Michelle Ulrich3
1Department of Medicine III, University Hospital LMU Munich, Munich, Germany.
Journal for Immunotherapy of Cancer
|December 4, 2025
Summary
CD70 is a promising target for acute myeloid leukemia (AML) immunotherapy. However, interferon-gamma (IFN-γ) can induce resistance by upregulating HLA molecules, necessitating combination strategies for effective treatment.
Area of Science:
- Immunology and Cancer Therapeutics
- Molecular Biology and Genetics
- Hematology
Background:
- Developing immunotherapies for acute myeloid leukemia (AML) is challenging due to the need for specific target antigens to avoid on-target-off-leukemia toxicity.
- CD70 is expressed on AML bulk and leukemic stem cells, with limited expression on healthy cells, making it a potential immunotherapy target.
Purpose of the Study:
- To evaluate CD70 as a target for natural killer (NK)-cell-based immunotherapy in AML.
- To investigate the impact of cytokines on CD70 expression and NK-cell-mediated cytotoxicity.
Main Methods:
- Assessed CD70 surface expression in primary AML samples using multiparameter flow cytometry.
- Analyzed the cytotoxic capacity of a sugar-engineered anti-CD70 antibody (SEA-CD70) via antibody-dependent cellular cytotoxicity (ADCC) assays in AML models.
- Investigated cytokine effects on CD70 expression and ADCC using conditioned medium from activated T cells and recombinant cytokines.
Main Results:
- CD70 was expressed on a significant proportion of primary AML cells, with consistent expression at relapse.
- SEA-CD70 demonstrated potent dose-dependent cytotoxicity against AML cells in vitro and in vivo, correlating with CD70 levels.
- Tumor necrosis factor-alpha (TNF-α) upregulated CD70, enhancing ADCC, while interferon-gamma (IFN-γ) reduced ADCC by increasing NK inhibitory receptor ligands (HLA-ABC, HLA-E), indicating an inducible resistance mechanism.
Conclusions:
- CD70 is a viable target for NK-cell-based AML immunotherapy.
- IFN-γ-induced upregulation of HLA molecules on AML cells confers resistance to ADCC, highlighting an immune escape mechanism.
- Combination strategies are essential for clinical trials to overcome inducible immune resistance in AML immunotherapy.
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