title: Survivin blockade sensitizes rhabdomyosarcoma cells for lysis by fetal acetylcholine receptor-redirected T cells.
abstract: Cellular immunotherapy may provide a strategy to overcome the poor prognosis of metastatic and recurrent rhabdomyosarcoma (RMS) under the current regimen of polychemotherapy. Because little is known about resistance mechanisms of RMS to cytotoxic T cells, we investigated RMS cell lines and biopsy specimens for expression and function of immune costimulatory receptors and anti-apoptotic molecules by RT-PCR, Western blot analysis, IHC, and cytotoxicity assays using siRNA or transfection-modified RMS cell lines, together with engineered RMS-directed cytotoxic T cells specific for the fetal acetylcholine receptor. We found that costimulatory CD80 and CD86 were consistently absent from all RMSs tested, whereas inducible T-cell co-stimulator ligand (ICOS-L; alias B7H2) was expressed by a subset of RMSs and was inducible by tumor necrosis factor α in two of five RMS cell lines. Anti-apoptotic survivin, along with other inhibitor of apoptosis (IAP) family members (cIAP1, cIAP2, and X-linked inhibitor of apoptosis protein), was overexpressed by RMS cell lines and biopsy specimens. Down-regulation of survivin by siRNA or pharmacologically in RMS cells increased their susceptibility toward a T-cell attack, whereas induction of ICOS-L did not. Treatment of RMS-bearing Rag(-/-) mice with fetal acetylcholine receptor-specific chimeric T cells delayed xenograft growth; however, this happened without definitive tumor eradication. Combined blockade of survivin and application of chimeric T cells in vivo suppressed tumor proliferation during survivin inhibition. In conclusion, survivin blockade provides a strategy to sensitize RMS cells for T-cell-based therapy.
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Simon-Keller
authors.forename: Annette
authors.initials: A
authors.lastname: Paschen
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Hombach
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Stefan B
authors.initials: SB
authors.lastname: Eichmüller
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
authors.forename: Stefan
authors.initials: S
authors.lastname: Gattenlöhner
authors.forename: Florian
authors.initials: F
authors.lastname: Hoppe
authors.forename: Ivo
authors.initials: I
authors.lastname: Leuschner
authors.forename: Sabine
authors.initials: S
authors.lastname: Stegmaier
authors.forename: Ewa
authors.initials: E
authors.lastname: Koscielniak
authors.forename: Martin
authors.initials: M
authors.lastname: Leverkus
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D001706:Biopsy; D018106:CD28 Antigens / Q000276:immunology; D002675:Child, Preschool; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000096:biosynthesis / Q000276:immunology; D007223:Infant; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D011950:Receptors, Cholinergic / Q000276:immunology*; D012208:Rhabdomyosarcoma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction / Q000276:immunology; D000077022:Survivin; D013601:T-Lymphocytes / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; C107489:BIRC5 protein, human; D018106:CD28 Antigens; D061025:Costimulatory and Inhibitory T-Cell Receptors; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D011950:Receptors, Cholinergic; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha
references.citation: Diagn Mol Pathol. 1998 Jun;7(3):129-34
references.pmid: 9836066
references.citation: J Exp Med. 2001 Nov 5;194(9):1339-48
references.pmid: 11696598
references.citation: Int J Cancer. 2010 Nov 15;127(10):2467-77
references.pmid: 20225320
references.citation: J Clin Oncol. 2008 Nov 10;26(32):5198-203
references.pmid: 18824702
references.citation: Mol Cancer Ther. 2011 Feb;10(2):221-32
references.pmid: 21216939
references.citation: Expert Opin Ther Targets. 2013 Feb;17(2):127-38
references.pmid: 23231343
references.citation: Cancer Cell. 2005 May;7(5):457-68
references.pmid: 15894266
references.citation: Pediatr Blood Cancer. 2011 Sep;57(3):406-14
references.pmid: 21254373
references.citation: Blood. 2007 May 1;109(9):3982-8
references.pmid: 17185461
references.citation: Cancer Res. 2004 Nov 1;64(21):8036-44
references.pmid: 15520213
references.citation: Clin Cancer Res. 2010 Dec 15;16(24):6150-8
references.pmid: 21041181
references.citation: Curr Med Chem. 2011;18(2):191-9
references.pmid: 21110807
references.citation: Pediatr Blood Cancer. 2010 Aug;55(2):352-5
references.pmid: 20582983
references.citation: Clin Cancer Res. 2008 Aug 1;14(15):4850-8
references.pmid: 18676758
references.citation: Biochem J. 2010 Sep 1;430(2):199-205
references.pmid: 20704571
references.citation: Haematologica. 2010 Sep;95(9):1579-86
references.pmid: 20378565
references.citation: Biochem Biophys Res Commun. 2011 Apr 15;407(3):450-5
references.pmid: 21397587
references.citation: Clin Cancer Res. 2010 Aug 1;16(15):3901-9
references.pmid: 20542985
references.citation: Cancer Treat Rev. 2010 Jun;36(4):318-27
references.pmid: 20223596
references.citation: Cancer Res. 2006 Jan 1;66(1):24-8
references.pmid: 16397210
references.citation: Gene Ther. 2011 Jan;18(1):62-72
references.pmid: 20944680
references.citation: J Mol Diagn. 1999 Nov;1(1):23-31
references.pmid: 11272905
references.citation: J Clin Oncol. 2009 Mar 20;27(9):1446-55
references.pmid: 19224858
references.citation: Blood. 2006 Nov 15;108(10):3434-40
references.pmid: 16868249
references.citation: J Biol Chem. 2010 Jun 11;285(24):18326-35
references.pmid: 20406824
references.citation: Oncogene. 2010 Dec 2;29(48):6367-77
references.pmid: 20818434
references.citation: Pediatr Blood Cancer. 2009 Oct;53(4):533-6
references.pmid: 19148945
references.citation: Am J Pathol. 1998 Feb;152(2):437-44
references.pmid: 9466570
references.citation: J Clin Oncol. 2008 Jan 20;26(3):406-13
references.pmid: 18202417
references.citation: Blood. 2012 Mar 22;119(12):2709-20
references.pmid: 22160384
references.citation: Oncogene. 2000 Jun 8;19(25):2921-9
references.pmid: 10871843
references.citation: Brain. 2003 May;126(Pt 5):1026-35
references.pmid: 12690043
references.citation: Methods Mol Biol. 2003;207:365-81
references.pmid: 12412486
references.citation: J Med Genet. 2006 Feb;43(2):119-28
references.pmid: 15908567
references.citation: FASEB J. 2004 Jan;18(1):206-8
references.pmid: 14597555
references.citation: Nature. 1989 Jan 26;337(6205):311-2
references.pmid: 2911385
references.citation: J Immunol. 1999 Sep 15;163(6):2999-3006
references.pmid: 10477562
references.citation: J Biomed Biotechnol. 2010;2010:187621
references.pmid: 20204062
references.citation: J Biol Chem. 2004 Aug 13;279(33):34087-90
references.pmid: 15218035
references.citation: Nature. 2011 Dec 21;480(7378):480-9
references.pmid: 22193102
references.citation: Cell Immunol. 2003 Sep;225(1):53-63
references.pmid: 14643304
references.citation: Int J Oncol. 2011 Jan;38(1):279-85
references.pmid: 21109950
references.citation: Int J Cancer. 2000 Oct 1;88(1):115-20
references.pmid: 10962448
references.citation: J Clin Oncol. 2004 Dec 1;22(23):4787-94
references.pmid: 15570080
references.citation: Cancer Res. 2010 Mar 1;70(5):1825-34
references.pmid: 20179203
references.citation: J Immunol. 2001 Dec 1;167(11):6123-31
references.pmid: 11714771
references.citation: Cancer Chemother Pharmacol. 2011 Aug;68(2):505-11
references.pmid: 21079959
references.citation: Am J Pathol. 2010 Oct;177(4):2055-66
references.pmid: 20829439
references.citation: Cell Death Differ. 2010 Jan;17(1):54-60
references.pmid: 19590513