1. HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2 + Tumors.
- Author
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Medon M, Vidacs E, Vervoort SJ, Li J, Jenkins MR, Ramsbottom KM, Trapani JA, Smyth MJ, Darcy PK, Atadja PW, Henderson MA, Johnstone RW, and Haynes NM
- Subjects
- Animals, Biomarkers, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Disease Models, Animal, Drug Synergism, Humans, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Lymphocyte Count, Mice, Panobinostat, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Histone Deacetylase Inhibitors pharmacology, Hydroxamic Acids pharmacology, Immunity, Innate drug effects, Indoles pharmacology, Receptor, ErbB-2 antagonists & inhibitors, Trastuzumab pharmacology
- 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+ AU565pv xenografts 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 ., (©2017 American Association for Cancer Research.)- Published
- 2017
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