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HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2 Tumors

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HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2 Tumors Published OnlineFirst March 1, 2017; DOI: 10.1158/0008-5472.CAN-16-2247 Cancer Microenvironment and Immunology Research HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2þ Tumors Mikolaj Medon1,2, Eva Vidacs1, Stephin J Vervoort1, Jason Li3, Misty R. Jenkins4,5, Kelly M. Ramsbottom4, Joseph A. Trapani4,5, Mark J. Smyth6, Phillip K. Darcy4,5, Peter W. Atadja7, Michael A. Henderson2, Ricky W. Johnstone1,5,and Nicole M. Haynes1,5 Abstract þ Histone deacetylase inhibitors (HDACi) may engage host activity in trastuzumab-refractory HER2 tumors. In trastuzu- þ immunity as one basis for their antitumor effects. Herein, we mab-resistant HER2 AU565pv xenografts and BT474 tumors demonstrate an application of this concept using the HDACi expressing constitutively active AKT, panobinostat enhanced panobinostat to augment the antitumor efficacy of trastuzu- the antibody-dependent cell-mediated cytotoxicity function of mab (anti-HER2) therapy, through both tumor cell autono- trastuzumab. IFNg–mediated, CXCR3-dependent increases in þ mous and nonautonomous mechanisms. In HER2 tumors tumor-associated NK cells underpinned the combined curative that are inherently sensitive to the cytostatic effects of trastu- activity of panobinostat and trastuzumab in these tumors. zumab, cotreatment with panobinostat abrogated AKT signal- These data highlight the immune-enhancing effects of pano- ing and triggered tumor regression in mice that lacked innate binostat and provide compelling evidence that this HDACi can and/or adaptive immune effector cells. However, the cooper- license trastuzumab to evoke NK-cell–mediated responses þ ative ability of panobinostat and trastuzumab to harness host capable of eradicating trastuzumab-refractory HER2 tumors. anticancer immune defenses was essential for their curative Cancer Res; 77(10); 2594–606. Ó2017 AACR. Introduction mab (Herceptin) has substantially improved prognosis for HER2-positive breast cancer patients (3). By binding HER2, Approximately 20% to 30% of breast cancers overexpress the trastuzumab can induce cell-cycle arrest and/or inhibit DNA HER2/neu oncogene–encoding HER2 (1). Active dimers of repair (3). It can also trigger immune-mediated tumor cell death HER2 with other family members promote tumorigenesis by through antibody-dependent cell-mediated cytotoxicity (ADCC) enhancing tumor cell growth and survival (2). Targeted blockade and may evoke therapeutically beneficial adaptive immune of HER2 signaling with the humanized antibody (Ab) trastuzu- responses (4). However, despite these pleiotropic actions of þ trastuzumab, less than 35% of HER2 breast cancers demonstrate initial response to trastuzumab and of those patients with meta- 1Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian static disease who initially respond to anti-HER2-based chemo- 2 Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia. Division therapy, 70% relapse within a year of treatment initiation (5). of Surgical Oncology, Peter MacCallum Cancer Centre, VCCC, Melbourne, Histone deacetylase inhibitors (HDACi) are anticancer drugs Victoria, Australia. 3Bioinformatics Consulting Core Facility, Cancer Research Division, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia. that can mediate a diverse array of biological responses, including 4Cancer Immunology Research Program, Peter MacCallum Cancer Centre, induction of apoptosis and cell-cycle arrest, inhibition of angio- VCCC, Melbourne, Victoria, Australia. 5Sir Peter MacCallum Department of genesis, and promotion of tumor cell differentiation (6). From an Oncology, The University of Melbourne, Parkville, Victoria, Australia. 6Immu- immunological perspective, HDACi can modulate the effector nology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research functions of activated immune cells and promote the efficacy of 7 Institute, Herston, Queensland, Australia. China Novartis, Institute for Biomed- immunotherapeutic strategies in established solid tumors (7, 8). ical Research, Shanghai, China. HDACi may engage anticancer immune responses by directly Note: Supplementary data for this article are available at Cancer Research altering tumor cell immunogenicity, and have the potential to þ Online (http://cancerres.aacrjournals.org/). rescue the functional activity of exhausted CD8 T cells (9, 10). By N.M. Haynes and R.W. Johnstone contributed equally and are co-senior authors modulating the activity and accumulation of regulatory immune of this article. cells in tumors, HDACi may also influence the immunosuppres- Corresponding Author: Nicole M. Haynes, Peter MacCallum Cancer Centre, sive nature of the tumor microenvironment (10). Victorian Comprehensive Cancer Centre, 305 Grattan Street, Melbourne, Vic- HDACi have been shown to potentiate the antitumor effects toria 3000, Australia. Phone: 613-8559-7127; Fax: 613-8559-5039; E-mail: of trastuzumab and lapatinib against trastuzumab-sensitive, [email protected] þ HER2 tumor cell lines in vitro (11–14). Such findings have doi: 10.1158/0008-5472.CAN-16-2247 established grounds for testing HDACi in combination Ó2017 American Association for Cancer Research. with trastuzumab and chemotherapy in early-phase clinical 2594 Cancer Res; 77(10) May 15, 2017 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst March 1, 2017; DOI: 10.1158/0008-5472.CAN-16-2247 Panobinostat Enhances the Curative Activity of Trastuzumab trials with promising activity (15, 16). Here, we examine the panobinostat or corresponding DMSO concentrations for 24– combined anticancer activity and mechanisms of synergy 48 hours or (ii) 1 mg/mL trastuzumab or control human IgG1 between trastuzumab and the HDACi panobinostat in models (Enzo Life Sciences) for 96 hours before addition of 20 nmol/L þ of trastuzumab-sensitive and -refractory HER2 cancer. We panobinostat or DMSO for 24 hours. Vehicle- and drug-treated demonstrate the novel curative capacity of this anti–HER2- cells were stained with Annexin-V-FITC (BD Pharmingen)/pro- based combination therapy and its ability to engage host pidium iodine (PI) and analyzed on a LSRII analyzer (BD Bios- innate immune cells and effector molecules to evoke durable ciences). Two replicate wells/group were analyzed. A 4-hour 51Cr þ therapeutic responses against trastuzumab-refractory HER2 release assay (as described; ref. 22) was used to assess the effects of tumors. panobinostat on NK-cell cytotoxicity and tumor cell sensitivity to NK-cell killing. IL2–activated mouse NK cells were: (i) cultured in 10 nmol/L panobinostat or DMSO for 20 hours before being Materials and Methods 51 51 cocultured with Cr-labeled target cells or (ii) cultured with Cr- Mice labeled targets that had been pretreated for 20 hours with 5–50 Six- to 8-week-old SCID mice were obtained from the Austra- nmol/L panobinostat. lian Resources Centre (Perth, Western Australia). NOD/SCID À À IL2Rg / (NSG) and BALB/c MMTV-Her2/neu transgenic mice Western blot analysis were bred in-house and genotyped at the Peter MacCallum Cancer Immunoblots were performed on whole-cell lysates (19). Centre (PMCC; ref. 17). All animal experiments were performed Tumor cell cultures were treated as outlined above in the presence in accordance with institutional guidelines of the PMCC. of 10 mmol/L qVD (InSolution Q-VD-OPh; Calbiochem). Pro- tein/sample was resolved on 10% SDS-PAGE gels. Antibodies Cell lines against human HER2 (tyr1248; Cell Signaling Technology), AKT The AU565 and BT474 cell lines were purchased from the ATCC (Cell Signaling Technology), pAKT (Ser473; 193H12; Cell Sig- (2009; both lines were last authenticated in July 2015). BT474 naling Technology), Bcl-2 (Cell Signaling Technology), and tumor cells were maintained in RPMI1640, 10% FBS, 2 mmol/L L- b-Actin (Sigma-Aldrich) were used as probes that were detected glutamine, 0.1 mmol/L nonessential amino acids, 1 mmol/L using horseradish peroxidase–conjugated secondary Abs (DAKO) sodium pyruvate, and 0.1 mmol/L HEPES. AU565 tumor cells and enhanced chemiluminescence (ECL, Amersham; Lumilight, were maintained in RPMI-1640, 10% FBS, 2 mmol/L L-glutamine Roche). and 0.1 mmol/L HEPES. Through multiple passages of the AU565 tumor line, we derived a variant (AU565pv) that could be xeno- grafted into NSG and SCID mice. MSCV-GFP/Bcl2 and MSCV- Therapy of transplanted tumors  6 pv  6 GFP/AKT (myristolated AKT (MyrAKT)) were transduced into the BT474 (3 10 ) or AU565 (1.5 10 ) tumor cells were BT474 and/or AU565pv cells as described previously (18–20). The orthotopically injected into the fourth mammary fat pad of SCID þ rat HER2 murine H2N100 and H2N113 mammary carcinoma or NSG mice. 0.72 mg estrogen pellets (Innovative Research of cell lines (derived from MMTV Her2/neu transgenic mice; ref. 21) America) were implanted subcutaneously at the time of BT474 and YAC-1 cell line were cultured in RPMI1640, 10% FBS, 2 tumor inoculation. In some experiments, tumor-free NSG mice  6 mmol/L L-glutamine and 0.1 mmol/L HEPES. All cell lines tested were reconstituted with 1.5 10 mouse splenic NK cells, twice – negative for Mycoplasma contamination by PCR. enriched (90% 95% purity) using an NK Cell Isolation Kit (StemCell Technologies). Seven days after NK-cell reconstitution, AU565pv tumor cells were orthotopically injected. A total of 5  Drugs and reagents 5 10 H2N100 or H2N113 tumor cells were injected subcutane- Trastuzumab (Herceptin,
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