title: Ectopic expression of X-linked lymphocyte-regulated protein pM1 renders tumor cells resistant to antitumor immunity.
abstract: Tumor immune escape is a major obstacle in cancer immunotherapy, but the mechanisms involved remain poorly understood. We have previously developed an immune evasion tumor model using an in vivo immune selection strategy and revealed Akt-mediated immune resistance to antitumor immunity induced by various cancer immunotherapeutic agents. In the current study, we used microarray gene analysis to identify an Akt-activating candidate molecule overexpressed in immune-resistant tumors compared with parental tumors. X-linked lymphocyte-regulated protein pM1 (XLR) gene was the most upregulated in immune-resistant tumors compared with parental tumor cells. Furthermore, the retroviral transduction of XLR in parental tumor cells led to activation of Akt, resulting in upregulation of antiapoptotic proteins and the induction of immune resistance phenotype in parental tumor cells. In addition, we found that transduction of parental tumor cells with other homologous genes from the mouse XLR family, such as synaptonemal complex protein 3 (SCP3) and XLR-related, meiosis-regulated protein (XMR) and its human counterpart of SCP3 (hSCP3), also led to activation of Akt, resulting in the upregulation of antiapoptotic proteins and induction of immune resistance phenotype. Importantly, characterization of a panel of human cervical cancers revealed relatively higher expression levels of hSCP3 in human cervical cancer tissue compared with normal cervical tissue. Thus, our data indicate that ectopic expression of XLR and its homologues in tumor cells represents a potentially important mechanism for tumor immune evasion and serves as a promising molecular target for cancer immunotherapy.
authors.affiliation: Divison of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea.
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Noh
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Bae
authors.forename: Ken Y
authors.initials: KY
authors.lastname: Lin
authors.forename: Archana
authors.initials: A
authors.lastname: Monie
authors.forename: Sara I
authors.initials: SI
authors.lastname: Pai
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005260:Female; D050172:Genes, X-Linked; D006801:Humans; D007107:Immune System; D007167:Immunotherapy / Q000379:methods; D008214:Lymphocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C490060:SYCP3 protein, human; C490062:Sycp3 protein, mouse; C490091:XLRL protein, human; C490092:Xlr nuclear protein, mouse
references.citation: Cancer Res. 2007 Feb 15;67(4):1832-41
references.pmid: 17308126
references.citation: Nat Med. 2004 Sep;10(9):909-15
references.pmid: 15340416
references.citation: Oncogene. 2005 Nov 14;24(50):7401-9
references.pmid: 16288287
references.citation: Biostatistics. 2003 Apr;4(2):249-64
references.pmid: 12925520
references.citation: Immunodefic Rev. 1991;2(4):283-302
references.pmid: 2059434
references.citation: Cancer Res. 2001 May 1;61(9):3698-703
references.pmid: 11325841
references.citation: Cancer Res. 2007 Jul 1;67(13):6003-6
references.pmid: 17616653
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11671-5
references.pmid: 8524826
references.citation: Int J Pharm. 2008 Feb 28;350(1-2):27-34
references.pmid: 17897800
references.citation: J Exp Med. 1987 Dec 1;166(6):1702-15
references.pmid: 3681192
references.citation: J Comput Biol. 2001;8(1):37-52
references.pmid: 11339905
references.citation: Cancer Res. 2004 Jul 1;64(13):4394-9
references.pmid: 15231645
references.citation: J Clin Invest. 2001 Sep;108(5):669-78
references.pmid: 11544272
references.citation: Mol Cell Biol. 1994 Feb;14(2):1137-46
references.pmid: 8289794
references.citation: Stat Med. 2003 Dec 30;22(24):3899-914
references.pmid: 14673946
references.citation: EMBO J. 1994 Jan 1;13(1):100-9
references.pmid: 8306953
references.citation: Mol Ther. 2009 Mar;17(3):439-47
references.pmid: 19107122
references.citation: Cancer Res. 2003 May 15;63(10):2393-8
references.pmid: 12750257
references.citation: J Exp Med. 1997 Feb 3;185(3):453-9
references.pmid: 9053445
references.citation: Oncogene. 2008 Oct 27;27(50):6473-88
references.pmid: 18955974
references.citation: Cancer Res. 2000 Feb 15;60(4):1035-42
references.pmid: 10706121
references.citation: Cancer Res. 1996 Jan 1;56(1):21-6
references.pmid: 8548765