Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity

Science. 2018 Mar 30;359(6383):1537-1542. doi: 10.1126/science.aao0505.

Abstract

MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Blocking / immunology
  • Antibodies, Blocking / therapeutic use*
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Histocompatibility Antigens Class I / chemistry
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Immunocompetence
  • Killer Cells, Natural / immunology*
  • Ligands
  • Melanoma / immunology
  • Melanoma / pathology
  • Melanoma / therapy*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • NK Cell Lectin-Like Receptor Subfamily K / immunology
  • Neoplasm Metastasis
  • Protein Domains / immunology
  • Receptors, IgG / immunology

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Histocompatibility Antigens Class I
  • KLRK1 protein, human
  • Ligands
  • MHC class I-related chain A
  • MICB antigen
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, IgG