title: A hypoxia-induced decrease of either MICA/B or Hsp70 on the membrane of tumor cells mediates immune escape from NK cells.
abstract: Recent findings suggest that hypoxia of the tumor microenvironment contributes to immune escape from natural killer (NK) cell-mediated cytotoxicity. Heat shock protein 70 (Hsp70) and the stress-regulated major histocompatibility class I chain-related protein A and B (MICA/B) both serve as ligands for activated NK cells when expressed on the cell surface of tumor cells. Herein, we studied the effects of hypoxia and hypoxia-inducible factor-1α (HIF-1α) on the membrane expression of these NK cell ligands in H1339 with high and MDA-MB-231 tumor cells with low basal HIF-1α levels and its consequences on NK cell-mediated cytotoxicity. We could show that a hypoxia-induced decrease in the membrane expression of MICA/B and Hsp70 on H1339 and MDA-MB-231 cells, respectively, is associated with a reduced sensitivity to NK cell-mediated lysis. A knockdown of HIF-1α revealed that the decreased surface expression of MICA/B under hypoxia is dependent on HIF-1α in H1339 cells with high basal HIF-1α levels. Hypoxia and HIF-1α did not affect the MICA/B expression in MDA-MB-231 cells but reduced the Hsp70 membrane expression which in turn also impaired NK cell recognition. Furthermore, we could show that the hypoxia-induced decrease in membrane Hsp70 is independent of HIF-1α in MDA-MB-231. Our data indicate that hypoxia-induced downregulation of both NK cell ligands MICA/B and Hsp70 impairs NK cell-mediated cytotoxicity, whereby only MICA/B appears to be regulated by HIF-1α.
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schilling
authors.forename: Fabian
authors.initials: F
authors.lastname: Tetzlaff
authors.forename: Sarah
authors.initials: S
authors.lastname: Konrad
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
mesh_terms: D017209:Apoptosis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D012333:RNA, Messenger; D034741:RNA, Small Interfering
references.citation: Cell Stress Chaperones. 2008 Summer;13(2):221-30
references.pmid: 18759005
references.citation: Curr Pharm Des. 2013;19(3):430-40
references.pmid: 22920897
references.citation: J Immunol. 2009 Apr 15;182(8):4800-8
references.pmid: 19342658
references.citation: J Cell Physiol. 2001 Aug;188(2):223-35
references.pmid: 11424089
references.citation: FASEB J. 2009 Aug;23(8):2467-77
references.pmid: 19289606
references.citation: EMBO J. 2012 Mar 21;31(6):1379-93
references.pmid: 22252129
references.citation: Int J Oncol. 2012 Dec;41(6):2005-12
references.pmid: 22992985
references.citation: J Cell Sci. 2009 May 15;122(Pt 10):1495-8
references.pmid: 19383717
references.citation: EMBO J. 2007 Mar 7;26(5):1221-33
references.pmid: 17304217
references.citation: Cancer Res. 2008 Jun 15;68(12):4746-53
references.pmid: 18559521
references.citation: J Immunol. 2006 Dec 1;177(11):7849-57
references.pmid: 17114456
references.citation: PLoS One. 2012;7(2):e31110
references.pmid: 22347438
references.citation: Nat Med. 2009 Mar;15(3):319-24
references.pmid: 19252501
references.citation: Cancer Res. 2012 Sep 15;72(18):4629-41
references.pmid: 22962263
references.citation: Clin Cancer Res. 2004 Jun 1;10(11):3699-707
references.pmid: 15173076
references.citation: Front Immunol. 2012 Sep 25;3:299
references.pmid: 23056001
references.citation: Int J Hyperthermia. 2010;26(3):232-46
references.pmid: 20388021
references.citation: Cell Stress Chaperones. 2001 Oct;6(4):337-44
references.pmid: 11795470
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):733-8
references.pmid: 21187371
references.citation: J Biol Chem. 2012 Jan 13;287(3):2055-67
references.pmid: 22134923
references.citation: Life Sci. 2010 Jul 17;87(3-4):111-9
references.pmid: 20566410
references.citation: Cancer Res. 2011 Dec 15;71(24):7433-41
references.pmid: 22006996
references.citation: Int J Cancer. 1995 Apr 10;61(2):272-9
references.pmid: 7705958
references.citation: Strahlenther Onkol. 2012 Apr;188(4):353-8
references.pmid: 22318330
references.citation: Trends Immunol. 2008 Aug;29(8):397-403
references.pmid: 18602338
references.citation: Cancer Res. 2014 Feb 1;74(3):665-74
references.pmid: 24336068
references.citation: Cancer Res. 2005 Apr 1;65(7):2761-9
references.pmid: 15805276
references.citation: PLoS One. 2012;7(6):e37475
references.pmid: 22761656
references.citation: BMC Cancer. 2007 Jul 30;7:143
references.pmid: 17663760
references.citation: Cell Stress Chaperones. 2003 Winter;8(4):348-60
references.pmid: 15115287
references.citation: BMC Cell Biol. 2010 Nov 23;11:91
references.pmid: 21092233
references.citation: Cancer Res. 2005 Jun 15;65(12):5238-47
references.pmid: 15958569
references.citation: Cell Cycle. 2011 Apr 15;10(8):1249-60
references.pmid: 21412054