title: Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma.
abstract: Valpha24-invariant natural killer T (NKT) cells are potentially important for antitumor immunity. We and others have previously demonstrated positive associations between NKT cell presence in primary tumors and long-term survival in distinct human cancers. However, the mechanism by which aggressive tumors avoid infiltration with NKT and other T cells remains poorly understood. Here, we report that the v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN), the hallmark of aggressive neuroblastoma, repressed expression of monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2), a chemokine required for NKT cell chemoattraction. MYCN knockdown in MYCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction. Unlike other oncogenes, MYCN repressed chemokine expression in a STAT3-independent manner, requiring an E-box element in the CCL2 promoter to mediate transcriptional repression. MYCN overexpression in neuroblastoma xenografts in NOD/SCID mice severely inhibited their ability to attract human NKT cells, T cells, and monocytes. Patients with MYCN-amplified neuroblastoma metastatic to bone marrow had 4-fold fewer NKT cells in their bone marrow than did their nonamplified counterparts, indicating that the MYCN-mediated immune escape mechanism, which we believe to be novel, is operative in metastatic cancer and should be considered in tumor immunobiology and for the development of new therapeutic strategies.
authors: Division of Hematology-Oncology, Department of Pediatrics, Childrens Hospital Los Angeles (CHLA), Los Angeles, California 90027, USA.
authors: Liping
authors: L
authors: Song
authors: Tasnim
authors: T
authors: Ara
authors: Hong-Wei
authors: HW
authors: Wu
authors: Chan-Wook
authors: CW
authors: Woo
authors: C Patrick
authors: CP
authors: Reynolds
authors: Robert C
authors: RC
authors: Seeger
authors: Yves A
authors: YA
authors: DeClerck
authors: Carol J
authors: CJ
authors: Thiele
authors: Richard
authors: R
authors: Sposto
authors: Leonid S
authors: LS
authors: Metelitsa
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D000071447:N-Myc Proto-Oncogene Protein; D009362:Neoplasm Metastasis / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018932:Chemokine CCL2; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D050796:STAT3 Transcription Factor
references: Cell. 1981 Feb;23(2):311-22
references: 6258797
references: Prog Clin Biol Res. 1988;271:291-306
references: 3406003
references: J Exp Med. 1989 Apr 1;169(4):1485-90
references: 2926331
references: EMBO J. 1991 Jan;10(1):133-41
references: 1989881
references: Science. 1991 Mar 8;251(4998):1211-7
references: 2006410
references: Nat Rev Immunol. 2002 Dec;2(12):982-7
references: 12461571
references: Clin Cancer Res. 2002 Dec;8(12):3702-9
references: 12473579
references: Nature. 2002 Dec 19-26;420(6917):860-7
references: 12490959
references: Trends Cell Biol. 2003 Mar;13(3):146-50
references: 12628347
references: J Mol Biol. 2003 May 16;328(5):977-83
references: 12729735
references: Cancer Res. 2003 Jun 15;63(12):3026-31
references: 12810621
references: J Exp Med. 2003 Jun 16;197(12):1667-76
references: 12796469
references: Blood. 2003 Sep 15;102(6):1951-8
references: 12730102
references: J Cell Physiol. 2003 Nov;197(2):157-68
references: 14502555
references: Mol Cancer Ther. 2003 Sep;2(9):911-7
references: 14555710
references: J Exp Med. 2003 Dec 1;198(11):1631-41
references: 14657217
references: J Exp Med. 2003 Dec 1;198(11):1741-52
references: 14657224
references: Blood. 2004 Jan 15;103(2):383-9
references: 14512316
references: Nat Med. 2004 Jan;10(1):48-54
references: 14702634
references: Nat Rev Cancer. 2004 Jan;4(1):71-8
references: 14708027
references: Clin Immunol. 2004 Mar;110(3):267-76
references: 15047204
references: Blood. 2004 Apr 15;103(8):2981-9
references: 15070674
references: J Exp Med. 2004 May 3;199(9):1213-21
references: 15123743
references: Immunol Cell Biol. 2004 Jun;82(3):323-31
references: 15186264
references: N Engl J Med. 1985 Oct 31;313(18):1111-6
references: 4047115
references: J Immunol. 2001 Dec 1;167(11):6525-32
references: 11714821
references: Cytometry. 2001 Nov 1;45(3):194-205
references: 11746088
references: Curr Opin Immunol. 2002 Apr;14(2):165-71
references: 11869887
references: J Immunol. 2002 Jun 15;168(12):6494-9
references: 12055270
references: Blood. 2002 Jul 1;100(1):11-6
references: 12070001
references: Trends Immunol. 2002 Nov;23(11):516-9
references: 12401396
references: Blood. 1991 Aug 15;78(4):1112-6
references: 1868242
references: J Immunol. 2001 Sep 15;167(6):3114-22
references: 11544296
references: Diagn Mol Pathol. 1992 Dec;1(4):229-34
references: 1342970
references: Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3652-6
references: 8170963
references: Cancer. 1994 Nov 1;74(9):2403-13
references: 7922993
references: Br J Cancer. 1996 Sep;74(5):670-6
references: 8845294
references: EMBO J. 1997 Jun 2;16(11):2985-95
references: 9214616
references: Eur J Immunol. 1998 Jan;28(1):104-13
references: 9485190
references: Eur J Immunol. 1998 Oct;28(10):3221-30
references: 9808191
references: Mol Cell Biol. 1999 Jan;19(1):1-11
references: 9858526
references: J Clin Invest. 2004 Nov;114(10):1379-88
references: 15545985
references: Blood. 2004 Dec 15;104(13):4150-6
references: 15328159
references: Methods Enzymol. 2005;392:218-26
references: 15644184
references: Annu Rev Immunol. 2005;23:877-900
references: 15771592
references: J Exp Med. 2005 May 2;201(9):1503-17
references: 15867097
references: Curr Biol. 2005 Jun 7;15(11):R429-31
references: 15936267
references: Trends Immunol. 2005 Jul;26(7):360-6
references: 15978522
references: Crit Rev Immunol. 2005;25(3):183-213
references: 16048435
references: Clin Cancer Res. 2005 Oct 15;11(20):7322-7
references: 16243803
references: J Exp Med. 2005 Nov 21;202(10):1399-410
references: 16287709
references: J Exp Med. 2005 Dec 19;202(12):1627-33
references: 16365146
references: N Engl J Med. 2005 Dec 22;353(25):2654-66
references: 16371631
references: Nat Rev Cancer. 2006 Jan;6(1):24-37
references: 16397525
references: Nat Rev Immunol. 2007 Jan;7(1):41-51
references: 17186030
references: J Clin Oncol. 2007 Mar 1;25(7):862-8
references: 17327607
references: Curr Opin Immunol. 2007 Apr;19(2):224-31
references: 17303400
references: Oncogene. 1999 May 13;18(19):3004-16
references: 10378696
references: Annu Rev Cell Dev Biol. 2000;16:653-99
references: 11031250
references: Nat Immunol. 2000 Dec;1(6):515-20
references: 11101874
references: Nat Immunol. 2001 Apr;2(4):293-9
references: 11276199
references: Br J Haematol. 2001 Mar;112(4):945-9
references: 11298589
references: J Immunol. 2001 Oct 1;167(7):4046-50
references: 11564825
references: J Immunol. 2001 Nov 15;167(10):5531-4
references: 11698421
references: J Immunol. 2004 Jun 15;172(12):7629-34
references: 15187143
references: J Exp Med. 2004 Jun 21;199(12):1607-18
references: 15197224
references: J Leukoc Biol. 2004 Aug;76(2):307-13
references: 15123775
references: Immunity. 2004 Aug;21(2):137-48
references: 15308095
references: Cancer Res. 1977 May;37(5):1364-71
references: 856461