{
  "abstract": "Background 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.Methods This study evaluated CD70 as a target for NK-cell-based immunotherapy using a sugar-engineered antibody (PF-08046040, SEA-CD70). CD70 surface expression was assessed in primary AML samples by multiparameter flow cytometry. The cytotoxic capacity of SEA-CD70 was analyzed through antibody-dependent cellular cytotoxicity (ADCC) assays using AML cell lines, primary AML samples, and a severe combined immunodeficiency (SCID) mouse xenograft model. The effects of cytokines on CD70 expression and ADCC were investigated by exposing AML cells to conditioned medium (CM) derived from activated T cells or recombinant cytokines.Results 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 unchanged 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 CM from activated T cells upregulated CD70. TNF-α was identified as the driver of CD70 upregulation, translating into enhanced ADCC against AML cells (cytotoxicity w/o TNF-α = 17.9% vs with TNF-α = 34.3%, n=13–15). Conversely, IFN-γ exposure led to reduced ADCC (cytotoxicity w/o IFN-γ = 17.9% vs with IFN-γ = 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.Conclusions CD70 is a promising target for NK cell-based immunotherapy in AML. However, IFN-γ-dependent upregulation of HLA molecules on AML cells contributes to resistance to ADCC. These findings underscore the need for rationale combination strategies in clinical trials to overcome this inducible immune escape mechanism.",
  "authors": [
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Monika Sponheimer"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Kieron White"
    },
    {
      "affiliations": [
        "Pfizer Inc, New York, New York, USA"
      ],
      "name": "Michelle Ulrich"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Maryam Kazerani"
    },
    {
      "affiliations": [
        "Faculty of Biology and Center for Molecular Biosystems (BioSysM), LMU Munich, Munich, Germany"
      ],
      "name": "Andreas Maiser"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Emil Thore Tyborski"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Giulia Petra Rappa"
    },
    {
      "affiliations": [
        "Faculty of Biology, Anthropology & Human Genomics, LMU Munich, Munich, Germany"
      ],
      "name": "Daniel Richter"
    },
    {
      "affiliations": [
        "Faculty of Biology, Anthropology & Human Genomics, LMU Munich, Munich, Germany"
      ],
      "name": "Eva Briem"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Gerulf Hänel"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Nora Philipp"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Daniel Nixdorf"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Lisa Rohrbacher"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Anetta Marcinek"
    },
    {
      "affiliations": [
        "Department of Biochemistry, LMU Munich Gene Center, Munich, Germany"
      ],
      "name": "Andreas Linder"
    },
    {
      "affiliations": [
        "Department of Biochemistry, LMU Munich Gene Center, Munich, Germany"
      ],
      "name": "Niklas Kuhl"
    },
    {
      "affiliations": [
        "Department of Biochemistry, LMU Munich Gene Center, Munich, Germany",
        "Department of Medicine II, University Hospital LMU Munich, Munich, Germany"
      ],
      "name": "Ignazio Piseddu"
    },
    {
      "affiliations": [
        "Bioinformatics Unit, LMU Munich, Munich, Germany"
      ],
      "name": "Tobias Straub"
    },
    {
      "affiliations": [
        "Faculty of Biology and Center for Molecular Biosystems (BioSysM), LMU Munich, Munich, Germany"
      ],
      "name": "Hartmann Harz"
    },
    {
      "affiliations": [
        "Department of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital LMU Munich, Munich, Germany"
      ],
      "name": "Christian Wichmann"
    },
    {
      "affiliations": [
        "Department of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital LMU Munich, Munich, Germany"
      ],
      "name": "Denis Maenner"
    },
    {
      "affiliations": [
        "Institute of Pathology, University Hospital LMU Munich, Munich, Germany"
      ],
      "name": "Martina Rudelius"
    },
    {
      "affiliations": [
        "Department of Biochemistry, LMU Munich Gene Center, Munich, Germany"
      ],
      "name": "Veit Hornung"
    },
    {
      "affiliations": [
        "Faculty of Biology and Center for Molecular Biosystems (BioSysM), LMU Munich, Munich, Germany"
      ],
      "name": "Heinrich Leonhardt"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands",
        "Research Institute for Oncology and Reproduction (GROW), Maastricht University, Maastricht, The Netherlands"
      ],
      "name": "Catharina H M J Van Elssen"
    },
    {
      "affiliations": [
        "Pfizer Inc, New York, New York, USA"
      ],
      "name": "Sherif Abdelhamed"
    },
    {
      "affiliations": [
        "Pfizer Inc, New York, New York, USA"
      ],
      "name": "Daniel Diolaiti"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Veit Bücklein"
    },
    {
      "affiliations": [
        "Department of Medicine III, University Hospital LMU Munich, Munich, Germany",
        "Laboratory for Translational Cancer Immunology, LMU Munich Gene Center Munich, Munich, Germany"
      ],
      "name": "Marion Subklewe"
    }
  ],
  "title": "TNF-α and IFN-γ differentially regulate AML cell susceptibility to CD70-antibody-mediated cytotoxicity",
  "uid": "bfa97971-4bb4-5648-ba13-f89cf286eb54"
}