journal contribution posted on 2023-03-31, 00:30 authored by 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
Supplemental Figure Legend, Supplementary Figure 1 Flow cytometric analysis of HER2 expression on AU565pv and BT474 tumor cells; Supplementary Figure 2 Co-treatment with panobinostat and trastuzumab does not alter splenic NK cell activation/maturation status or frequency in AU565pv tumor-bearing SCID mice; Supplementary Figure 3 Panobinostat-mediated enrichment of interferon-gamma response and chemokine associated gene signatures; Supplementary Figure 4 SCID mice bearing AU565pv tumors were treated with PBS/DMSO (Vehicle), DMSO/trastuzumab (10 mg/kg), PBS/panobinostat (15 mg/kg) or panobinostat and trastuzumab (combination); Supplementary Figure 5 Panobinostat treatment modulates expression of both the activation receptor CD69 and Fc-receptors CD16/32 on IL-2 activated mouse and human NK cells; Supplementary Figure 6 Co-treatment of panobinostat and trastuzumab attenuates HER2 expression in BT474 and BT474-MyrAKT tumor cells; Supplementary Figure 7 Panobinostat is more effective than doxorubicin at supporting the curative activity of anti-HER2 therapy in Her2/neu transgenic mice bearing established rHER2+ H2N113 mammary tumors; Supplementary Figure 8 Rejection of Bcl-2 over-expressing AU565pv tumors in SCID mice treated with the combination therapy.
Victorian Breast Cancer Research Consortium
National Health and Medical Research Council of Australia
Cancer Council of Victoria
ARTICLE ABSTRACTHistone 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.