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 non-autonomous mechanisms. In HER2+ tumors that are inherently sensitive to the cytostatic effects of trastuzumab, co-treatment 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 anti-cancer 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. IFN-gamma 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.
- Received August 18, 2016.
- Revision received January 6, 2017.
- Accepted February 27, 2017.
- Copyright ©2017, American Association for Cancer Research.