Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages

Cell. 2018 Oct 4;175(2):442-457.e23. doi: 10.1016/j.cell.2018.09.007.


Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2+ breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.

Keywords: DNA sensor; IDO; PD-L1; antibody-dependent cellular phagocytosis; immune checkpoint inhibitors; inflammasome; macrophages; therapeutic antibodies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Antibody-Dependent Cell Cytotoxicity / immunology*
  • Antibody-Dependent Cell Cytotoxicity / physiology
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / physiology
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cytophagocytosis / immunology*
  • Cytophagocytosis / physiology
  • DNA-Binding Proteins / physiology
  • Disease Models, Animal
  • Female
  • Humans
  • Immunotherapy
  • Killer Cells, Natural / physiology
  • Lymphoma / immunology
  • Macrophages / immunology*
  • Macrophages / physiology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phagocytosis / immunology
  • Phagocytosis / physiology
  • Phagosomes / physiology
  • Receptors, IgG / immunology


  • AIM2 protein, human
  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • CD274 protein, human
  • DNA-Binding Proteins
  • Receptors, IgG