title: Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy.
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.
authors.affiliation: Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Stagg
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.forename: Upulie
authors.initials: U
authors.lastname: Divisekera
authors.forename: Shin Foong
authors.initials: SF
authors.lastname: Ngiow
authors.forename: Helene
authors.initials: H
authors.lastname: Duret
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Michele W
authors.initials: MW
authors.lastname: Teng
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000954:Antigens, Surface; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D045744:Cell Line, Tumor; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000276:immunology*; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology; D000068878:Trastuzumab; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D007370:Interferon Type I; D007371:Interferon-gamma; D061026:Programmed Cell Death 1 Receptor; D018719:Erb-b2 Receptor Tyrosine Kinases; D053573:Receptors, Interleukin-1 Type I; D053722:Receptors, Interleukin-17; D000068878:Trastuzumab; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C491673:Il17ra protein, mouse; C491383:Pdcd1 protein, mouse; C524056:Erbb2 protein, mouse