MARCH Proteins Mediate Responses to Antitumor Antibodies

J Immunol. 2020 Nov 15;205(10):2883-2892. doi: 10.4049/jimmunol.1901245. Epub 2020 Oct 19.


CD98, which is required for the rapid proliferation of both normal and cancer cells, and MET, the hepatocyte growth factor receptor, are potential targets for therapeutic antitumor Abs. In this study, we report that the antiproliferative activity of a prototype anti-CD98 Ab, UM7F8, is due to Ab-induced membrane-associated ring CH (MARCH) E3 ubiquitin ligase-mediated ubiquitination and downregulation of cell surface CD98. MARCH1-mediated ubiquitination of CD98 is required for UM7F8's capacity to reduce CD98 surface expression and its capacity to inhibit the proliferation of murine T cells. Similarly, CD98 ubiquitination is required for UM7F8's capacity to block the colony-forming ability of murine leukemia-initiating cells. To test the potential generality of the paradigm that MARCH E3 ligases can mediate the antiproliferative response to antitumor Abs, we examined the potential effects of MARCH proteins on responses to emibetuzumab, an anti-MET Ab currently in clinical trials for various cancers. We report that MET surface expression is reduced by MARCH1, 4, or 8-mediated ubiquitination and that emibetuzumab-induced MET ubiquitination contributes to its capacity to downregulate MET and inhibit human tumor cell proliferation. Thus, MARCH E3 ligases can act as cofactors for antitumor Abs that target cell surface proteins, suggesting that the MARCH protein repertoire of cells is a determinant of their response to such Abs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology
  • Antigens, Neoplasm / metabolism*
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Agents, Immunological / therapeutic use
  • Cell Proliferation / drug effects
  • Fusion Regulatory Protein 1, Heavy Chain / antagonists & inhibitors
  • Fusion Regulatory Protein 1, Heavy Chain / genetics
  • Fusion Regulatory Protein 1, Heavy Chain / immunology
  • Fusion Regulatory Protein 1, Heavy Chain / metabolism*
  • Gene Knockout Techniques
  • HeLa Cells
  • Humans
  • Jurkat Cells
  • Mice
  • Mice, Knockout
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Proteolysis
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / genetics
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / immunology


  • Antibodies, Monoclonal, Humanized
  • Antigens, Neoplasm
  • Antineoplastic Agents, Immunological
  • Fusion Regulatory Protein 1, Heavy Chain
  • Slc3A2 protein, mouse
  • Ubiquitin-Protein Ligases
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • emibetuzumab