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+ 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.

• Authors: Mikolaj Medon, Eva Vidacs, Stephin J Vervoort, Jason Li, Misty R Jenkins, Kelly M Ramsbottom, Joseph A Trapani, Mark J Smyth, Phillip K Darcy, Peter W Atadja, Michael A Henderson, Ricky W Johnstone, Nicole M Haynes
• Journal: Cancer research (Cancer Res) Vol. 77 Issue 10 Pg. 2594-2606 (05 15 2017) ISSN: 1538-7445 [Electronic] United States
• PMID: 28249907 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biomarkers
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Indoles
• Panobinostat
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-akt
• Trastuzumab

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Biomarkers
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease Models, Animal
• Drug Synergism
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Immunity, Innate (drug effects)
• Indoles (pharmacology)
• Killer Cells, Natural (drug effects, immunology, metabolism)
• Lymphocyte Count
• Mice
• Panobinostat
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Signal Transduction
• Trastuzumab (pharmacology)
• Xenograft Model Antitumor Assays