title: Trogocytosis-mediated expression of HER2 on immune cells may be associated with a pathological complete response to trastuzumab-based primary systemic therapy in HER2-overexpressing breast cancer patients.
abstract: BACKGROUND
  Trogocytosis is defined as the transfer of cell-surface membrane proteins and membrane patches from one cell to another through contact. It is reported that human epidermal growth factor receptor 2 (HER2) could be transferred from cancer cells to monocytes via trogocytosis; however, the clinical significance of this is unknown. The aim of this study is to demonstrate the presence and evaluate the clinical significance of HER2(+) tumor-infiltrated immune cells (arising through HER2 trogocytosis) in HER2-overexpressing (HER2+) breast cancer patients receiving trastuzumab-based primary systemic therapy (PST).
  
  
  METHODS
  To assess the trogocytosis of HER2 from cancer cells to immune cells, and to evaluate the up- and down-regulation of HER2 on immune and cancer cells, peripheral blood mononuclear cells from healthy volunteers and breast cancer patients were co-cultured with HER2+ and HER2-negative breast cancer cell lines with and without trastuzumab, respectively. The correlation between HER2 expression on tumor-infiltrated immune cells and a pathological complete response (pCR) in HER2+ breast cancer patients treated with trastuzumab-based PST was analyzed.
  
  
  RESULTS
  HER2 was transferred from HER2+ breast cancer cells to monocytes and natural killer cells by trogocytosis. Trastuzumab-mediated trogocytosed-HER2(+) effector cells exhibited greater CD107a expression than non-HER2-trogocytosed effector cells. In breast cancer patients, HER2 expression on tumor-infiltrated immune cells in treatment naïve HER2+ tumors was associated with a pCR to trastuzumab-based PST.
  
  
  CONCLUSIONS
  HER2-trogocytosis is visible evidence of tumor microenvironment interaction between cancer cells and immune cells. Given that effective contact between these cells is critical for immune destruction of target cancer cells, this interaction is of great significance. It is possible that HER2 trogocytosis could be used as a predictive biomarker for trastuzumab-based PST efficacy in HER2(+) breast cancer patients.
authors: Department of Breast Surgery, Kyoto University Hospital, 54 Shogoin kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. eijis@kuhp.kyoto-u.ac.jp.
authors: Eiji
authors: E
authors: Suzuki
authors: Department of Diagnostic Pathology, Kyoto University Hospital, 54 Shogoin kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. trkata@kuhp.kyoto-u.ac.jp.
authors: Tatsuki R
authors: TR
authors: Kataoka
authors: Department of Diagnostic Pathology, Kyoto University Hospital, 54 Shogoin kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. hiratama@kuhp.kyoto-u.ac.jp.
authors: Masahiro
authors: M
authors: Hirata
authors: Department of Breast Surgery, Kyoto University Hospital, 54 Shogoin kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. kkosuke@kuhp.kyoto-u.ac.jp.
authors: Kosuke
authors: K
authors: Kawaguchi
authors: Department of Breast Surgery, Kyoto University Hospital, 54 Shogoin kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. nishie@kuhp.kyoto-u.ac.jp.
authors: Mariko
authors: M
authors: Nishie
authors: Department of Diagnostic Pathology, Kyoto University Hospital, 54 Shogoin kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. haga@kuhp.kyoto-u.ac.jp.
authors: Hironori
authors: H
authors: Haga
authors: Department of Breast Surgery, Kyoto University Hospital, 54 Shogoin kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. toi@kuhp.kyoto-u.ac.jp.
authors: Masakazu
authors: M
authors: Toi
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019002:CD56 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D014176:Protein Biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D019002:CD56 Antigen; D018950:Lipopolysaccharide Receptors; D052118:Lysosomal-Associated Membrane Protein 1; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
references: Ann Oncol. 2015 Feb;26(2):259-71
references: 25214542
references: Cancer Res. 2008 Mar 15;68(6):2006-13
references: 18339883
references: J Immunol. 2008 Dec 1;181(11):8120-32
references: 19018005
references: Ann Oncol. 2011 Jun;22(6):1302-7
references: 21109570
references: Blood. 2012 Sep 6;120(10):2055-63
references: 22705596
references: Br J Cancer. 2013 Nov 12;109(10):2705-13
references: 24129232
references: PLoS One. 2013;8(12):e79775
references: 24312450
references: J Clin Oncol. 2014 Nov 20;32(33):3753-61
references: 25332247
references: Science. 1999 Oct 29;286(5441):952-4
references: 10542149
references: J Immunol. 2001 Feb 15;166(4):2505-13
references: 11160311
references: J Exp Med. 2001 Nov 19;194(10):1507-17
references: 11714757
references: Clin Cancer Res. 2002 Feb;8(2):347-53
references: 11839648
references: FASEB J. 2002 Apr;16(6):477-86
references: 11919150
references: Vet Immunol Immunopathol. 2004 Apr;98(3-4):203-14
references: 15010229
references: J Exp Med. 1976 Sep 1;144(3):788-809
references: 1085341
references: Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16873-8
references: 15550544
references: N Engl J Med. 2005 Oct 20;353(16):1659-72
references: 16236737
references: N Engl J Med. 2005 Oct 20;353(16):1673-84
references: 16236738
references: Clin Cancer Res. 2006 Jan 15;12(2):424-31
references: 16428482
references: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1428-33
references: 16432193
references: Crit Rev Immunol. 2006;26(1):1-21
references: 16472066
references: N Engl J Med. 2006 Feb 23;354(8):809-20
references: 16495393
references: Blood. 2007 Mar 1;109(5):2040-8
references: 17077329
references: Nat Rev Immunol. 2007 Mar;7(3):238-43
references: 17290299
references: Stem Cells. 2007 Jun;25(6):1560-70
references: 17332513
references: Scand J Immunol. 2007 Oct;66(4):441-50
references: 17850589
references: Cell Mol Immunol. 2008 Aug;5(4):261-9
references: 18761813