Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy

Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7142-7. doi: 10.1073/pnas.1016569108. Epub 2011 Apr 11.

Abstract

Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2/ErbB-2), has become the mainstay of treatment for HER2-positive breast cancer. Nevertheless, its exact mechanism of action has not been fully elucidated. Although several studies suggest that Fc receptor-expressing immune cells are involved in trastuzumab therapy, the relative contribution of lymphocyte-mediated cellular cytotoxicity and antitumor cytokines remains unknown. We report here that anti-ErbB-2 mAb therapy is dependent on the release of type I and type II IFNs but is independent of perforin or FasL. Our study thus challenges the notion that classical antibody-dependent, lymphocyte-mediated cellular cytotoxicity is important for trastuzumab. We demonstrate that anti-ErbB-2 mAb therapy of experimental tumors derived from MMTV-ErbB-2 transgenic mice triggers MyD88-dependent signaling and primes IFN-γ-producing CD8+ T cells. Adoptive cell transfer of purified T cell subsets confirmed the essential role of IFN-γ-producing CD8+ T cells. Notably, anti-ErbB-2 mAb therapy was independent of IL-1R or IL-17Ra signaling. Finally, we investigated whether immunostimulatory approaches with antibodies against programmed death-1 (PD-1) or 41BB (CD137) could be used to capitalize on the immune-mediated effects of trastuzumab. We demonstrate that anti-PD-1 or anti-CD137 mAb can significantly improve the therapeutic activity of anti-ErbB-2 mAb in immunocompetent mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antigens, Surface*
  • Antineoplastic Combined Chemotherapy Protocols / immunology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis Regulatory Proteins*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Line, Tumor
  • Humans
  • Interferon Type I / genetics
  • Interferon Type I / immunology*
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Mammary Neoplasms, Animal / drug therapy*
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Mice, Transgenic
  • Programmed Cell Death 1 Receptor
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / immunology*
  • Receptors, Interleukin-1 Type I / genetics
  • Receptors, Interleukin-1 Type I / immunology*
  • Receptors, Interleukin-17 / genetics
  • Receptors, Interleukin-17 / immunology
  • Trastuzumab
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology*

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • Il17ra protein, mouse
  • Interferon Type I
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Interleukin-1 Type I
  • Receptors, Interleukin-17
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Interferon-gamma
  • Erbb2 protein, mouse
  • Receptor, ErbB-2
  • Trastuzumab