{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T11:33:19Z","timestamp":1778326399577,"version":"3.51.4"},"reference-count":51,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2020,1,2]],"date-time":"2020-01-02T00:00:00Z","timestamp":1577923200000},"content-version":"unspecified","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Research funds of Medical University of Vienna"},{"name":"Research fund of the Fellinger Cancer Research"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>VPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (Fc\u03b3R) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the \u201cdo not eat me\u201d signal CD47 on tumor cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>HDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.<\/jats:p><\/jats:sec>","DOI":"10.1136\/jitc-2019-000195","type":"journal-article","created":{"date-parts":[[2020,1,7]],"date-time":"2020-01-07T18:39:17Z","timestamp":1578422357000},"page":"e000195","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":43,"title":["Histone deacetylase inhibitors valproic acid and vorinostat enhance trastuzumab-mediated antibody-dependent cell-mediated phagocytosis"],"prefix":"10.1136","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4771-1398","authenticated-orcid":false,"given":"Johannes","family":"Laengle","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julijan","family":"Kabiljo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leah","family":"Hunter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakob","family":"Homola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Prodinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2489-155X","authenticated-orcid":false,"given":"Gerda","family":"Egger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8529-1166","authenticated-orcid":false,"given":"Michael","family":"Bergmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2020,1,2]]},"reference":[{"key":"2020061616124942000_8.1.e000195.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0910383"},{"key":"2020061616124942000_8.1.e000195.2","doi-asserted-by":"crossref","first-page":"v8","DOI":"10.1093\/annonc\/mdv298","article-title":"Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up","volume":"26 Suppl 5","author":"Senkus","year":"2015","journal-title":"Ann Oncol"},{"key":"2020061616124942000_8.1.e000195.3","doi-asserted-by":"crossref","unstructured":"Vu T , Claret FX . Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol 2012;2:62.doi:10.3389\/fonc.2012.00062","DOI":"10.3389\/fonc.2012.00062"},{"key":"2020061616124942000_8.1.e000195.4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.22.1507"},{"key":"2020061616124942000_8.1.e000195.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc072213"},{"key":"2020061616124942000_8.1.e000195.6","doi-asserted-by":"publisher","DOI":"10.1038\/74704"},{"key":"2020061616124942000_8.1.e000195.7","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402891"},{"key":"2020061616124942000_8.1.e000195.8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.01.014"},{"key":"2020061616124942000_8.1.e000195.9","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.3.719"},{"key":"2020061616124942000_8.1.e000195.10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI69738"},{"key":"2020061616124942000_8.1.e000195.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0109-9"},{"key":"2020061616124942000_8.1.e000195.12","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-0344"},{"key":"2020061616124942000_8.1.e000195.13","doi-asserted-by":"crossref","unstructured":"Bolden JE , Shi W , Jankowski K , et al . HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses. Cell Death Dis 2013;4:e519.doi:10.1038\/cddis.2013.9","DOI":"10.1038\/cddis.2013.9"},{"key":"2020061616124942000_8.1.e000195.14","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.24.6969"},{"key":"2020061616124942000_8.1.e000195.15","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2247"},{"key":"2020061616124942000_8.1.e000195.16","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-0890"},{"key":"2020061616124942000_8.1.e000195.17","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4252"},{"key":"2020061616124942000_8.1.e000195.18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1011037108"},{"key":"2020061616124942000_8.1.e000195.19","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0599"},{"key":"2020061616124942000_8.1.e000195.20","first-page":"985","article-title":"Trastuzumab enhances the anti-tumor effects of the histone deacetylase inhibitor sodium butyrate on a HER2-overexpressing breast cancer cell line","volume":"28","author":"Chen","year":"2011","journal-title":"Int J Mol Med"},{"key":"2020061616124942000_8.1.e000195.21","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.canlet.2011.03.019","article-title":"HDAC inhibitor SNDX-275 enhances efficacy of trastuzumab in erbB2-overexpressing breast cancer cells and exhibits potential to overcome trastuzumab resistance","volume":"307","author":"Huang","year":"2011","journal-title":"Cancer Lett"},{"key":"2020061616124942000_8.1.e000195.22","first-page":"971","article-title":"Histone deacetylase inhibitor LAQ824 down-regulates HER-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B","volume":"2","author":"Fuino","year":"2003","journal-title":"Mol Cancer Ther"},{"key":"2020061616124942000_8.1.e000195.23","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s10549-017-4310-9","article-title":"A phase I\/II study of suberoylanilide hydroxamic acid (SAHA) in combination with trastuzumab (Herceptin) in patients with advanced metastatic and\/or local chest wall recurrent HER2-amplified breast cancer: a trial of the ECOG-ACRIN cancer research Group (E1104)","volume":"165","author":"Goldstein","year":"2017","journal-title":"Breast Cancer Res Treat"},{"key":"2020061616124942000_8.1.e000195.24","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.302"},{"key":"2020061616124942000_8.1.e000195.25","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2939"},{"key":"2020061616124942000_8.1.e000195.26","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.it.2017.12.005","article-title":"SIRP\u03b1-CD47 immune checkpoint blockade in anticancer therapy","volume":"39","author":"Veillette","year":"2018","journal-title":"Trends Immunol"},{"key":"2020061616124942000_8.1.e000195.27","doi-asserted-by":"publisher","DOI":"10.1038\/nm1523"},{"key":"2020061616124942000_8.1.e000195.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2007.04.009"},{"key":"2020061616124942000_8.1.e000195.29","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-008-0607-1"},{"key":"2020061616124942000_8.1.e000195.30","doi-asserted-by":"crossref","unstructured":"Petricevic B , Laengle J , Singer J , et al . Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2\/neu breast cancer patients. J Transl Med 2013;11:307.doi:10.1186\/1479-5876-11-307","DOI":"10.1186\/1479-5876-11-307"},{"key":"2020061616124942000_8.1.e000195.31","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(86)90837-8"},{"key":"2020061616124942000_8.1.e000195.32","doi-asserted-by":"crossref","unstructured":"Chao MP , Jaiswal S , Weissman-Tsukamoto R , et al . Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med 2010;2:63ra94.doi:10.1126\/scitranslmed.3001375","DOI":"10.1126\/scitranslmed.3001375"},{"key":"2020061616124942000_8.1.e000195.33","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/s41416-019-0473-y","article-title":"A phase Ib study of entinostat plus lapatinib with or without trastuzumab in patients with HER2-positive metastatic breast cancer that progressed during trastuzumab treatment","volume":"120","author":"Lim","year":"2019","journal-title":"Br J Cancer"},{"key":"2020061616124942000_8.1.e000195.34","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.26.2154"},{"key":"2020061616124942000_8.1.e000195.35","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.19.7939"},{"key":"2020061616124942000_8.1.e000195.36","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdt275"},{"key":"2020061616124942000_8.1.e000195.37","doi-asserted-by":"crossref","unstructured":"Vilquin P , Donini CF , Villedieu M , et al . Microrna-125B upregulation confers aromatase inhibitor resistance and is a novel marker of poor prognosis in breast cancer. Breast Cancer Res 2015;17.doi:10.1186\/s13058-015-0515-1","DOI":"10.1186\/s13058-015-0515-1"},{"key":"2020061616124942000_8.1.e000195.38","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdr484"},{"key":"2020061616124942000_8.1.e000195.39","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.jim.2011.03.003","article-title":"Visualization and quantification of cytotoxicity mediated by antibodies using imaging flow cytometry","volume":"368","author":"Helguera","year":"2011","journal-title":"J Immunol Methods"},{"key":"2020061616124942000_8.1.e000195.40","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-03-0549"},{"key":"2020061616124942000_8.1.e000195.41","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-08-0201"},{"key":"2020061616124942000_8.1.e000195.42","doi-asserted-by":"publisher","DOI":"10.1021\/cb300455f"},{"key":"2020061616124942000_8.1.e000195.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"2020061616124942000_8.1.e000195.44","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-0754"},{"key":"2020061616124942000_8.1.e000195.45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1305569110"},{"key":"2020061616124942000_8.1.e000195.46","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3931"},{"key":"2020061616124942000_8.1.e000195.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.09.007"},{"key":"2020061616124942000_8.1.e000195.48","doi-asserted-by":"publisher","DOI":"10.1038\/nature22396"},{"key":"2020061616124942000_8.1.e000195.49","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1272"},{"key":"2020061616124942000_8.1.e000195.50","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-0799"},{"key":"2020061616124942000_8.1.e000195.51"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2019-000195","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T23:16:21Z","timestamp":1592349381000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2019-000195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12,20]]},"published-print":{"date-parts":[[2020,1]]}},"alternative-id":["10.1136\/jitc-2019-000195"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2019-000195","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1]]}}}