Ectopic expression of X-linked lymphocyte-regulated protein pM1 renders tumor cells resistant to antitumor immunity.
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.
Kang
Tae Heung
TH
Divison of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea.
Noh
Kyung Hee
KH
Kim
Jin Hee
JH
Bae
Hyun Cheol
HC
Lin
Ken Y
KY
Monie
Archana
A
Pai
Sara I
SI
Hung
Chien-Fu
CF
Wu
T-C
TC
Kim
Tae Woo
TW
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
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
Cancer Res. 2007 Feb 15;67(4):1832-41
17308126
Nat Med. 2004 Sep;10(9):909-15
15340416
Oncogene. 2005 Nov 14;24(50):7401-9
16288287
Biostatistics. 2003 Apr;4(2):249-64
12925520
Immunodefic Rev. 1991;2(4):283-302
2059434
Cancer Res. 2001 May 1;61(9):3698-703
11325841
Cancer Res. 2007 Jul 1;67(13):6003-6
17616653
Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11671-5
8524826
Int J Pharm. 2008 Feb 28;350(1-2):27-34
17897800
J Exp Med. 1987 Dec 1;166(6):1702-15
3681192
J Comput Biol. 2001;8(1):37-52
11339905
Cancer Res. 2004 Jul 1;64(13):4394-9
15231645
J Clin Invest. 2001 Sep;108(5):669-78
11544272
Mol Cell Biol. 1994 Feb;14(2):1137-46
8289794
Stat Med. 2003 Dec 30;22(24):3899-914
14673946
EMBO J. 1994 Jan 1;13(1):100-9
8306953
Mol Ther. 2009 Mar;17(3):439-47
19107122
Cancer Res. 2003 May 15;63(10):2393-8
12750257
J Exp Med. 1997 Feb 3;185(3):453-9
9053445
Oncogene. 2008 Oct 27;27(50):6473-88
18955974
Cancer Res. 2000 Feb 15;60(4):1035-42
10706121
Cancer Res. 1996 Jan 1;56(1):21-6
8548765