title: HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2+Tumors.
abstract: Histone deacetylase inhibitors (HDACi) may engage host immunity as one basis for their antitumor effects. Herein, we demonstrate an application of this concept using the HDACi panobinostat to augment the antitumor efficacy of trastuzumab (anti-HER2) therapy, through both tumor cell autonomous and nonautonomous mechanisms. In HER2+tumors that are inherently sensitive to the cytostatic effects of trastuzumab, cotreatment with panobinostat abrogated AKT signaling and triggered tumor regression in mice that lacked innate and/or adaptive immune effector cells. However, the cooperative ability of panobinostat and trastuzumab to harness host anticancer immune defenses was essential for their curative activity in trastuzumab-refractory HER2+tumors. In trastuzumab-resistant HER2+AU565pvxenografts and BT474 tumors expressing constitutively active AKT, panobinostat enhanced the antibody-dependent cell-mediated cytotoxicity function of trastuzumab. IFNγ-mediated, CXCR3-dependent increases in tumor-associated NK cells underpinned the combined curative activity of panobinostat and trastuzumab in these tumors. These data highlight the immune-enhancing effects of panobinostat and provide compelling evidence that this HDACi can license trastuzumab to evoke NK-cell-mediated responses capable of eradicating trastuzumab-refractory HER2+tumors.Cancer Res; 77(10); 2594-606. ©2017 AACR.
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia.|Division of Surgical Oncology, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia.
authors.forename: Mikolaj
authors.initials: M
authors.lastname: Medon
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia.
authors.forename: Eva
authors.initials: E
authors.lastname: Vidacs
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia.
authors.forename: Stephin J
authors.initials: SJ
authors.lastname: Vervoort
authors.affiliation: Bioinformatics Consulting Core Facility, Cancer Research Division, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Misty R
authors.initials: MR
authors.lastname: Jenkins
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Ramsbottom
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
authors.affiliation: China Novartis, Institute for Biomedical Research, Shanghai, China.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Atadja
authors.affiliation: Division of Surgical Oncology, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Henderson
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia. nicole.haynes@petermac.org.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D000077767:Panobinostat; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D000068878:Trastuzumab / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab