Abstract
HLA-G belongs to the nonclassical MHC class Ib group of molecules and has been implicated in mediating immune-responsiveness in various cancerous and non-cancerous cell types. We have examined HLA-G expression in a number of human gastrointestinal malignancies, including pancreatic ductal adenocarcinoma, ampullary cancer, biliary cancer, and colorectal cancer by immunolabeling analysis. We used indices of <5% (negative), 6–25%, 26–50%, 51–75%, and >75% (diffuse) to subclassify lesions based on percentage of positive cell labeling. Across all cancer subtypes, 52–79% of lesions demonstrated expression of HLA-G, with up to 33% of lesions demonstrating diffuse (>75%) expression. In addition, we utilized the neoplastic progression model of colorectal cancer to evaluate HLA-G protein expression in normal colon, tubulovillous adenomas, invasive cancer, and liver metastases arising from colorectal cancer. Focal HLA-G expression was detected in regions of normal colon adjacent to sites of adenomatous and cancerous lesions, as well as in all stages of cancer progression. Overall, the percentage of diffusely (>75%) labeled lesions appeared increased in preneoplastic and neoplastic conditions, as compared to normal colon. Specifically, tubulovillous adnenomas demonstrated pronounced diffuse labeling in 58% of lesions examined. No correlation with HLA-G expression and CD4+ or CD8+ T cells was identified. We propose that HLA-G expression is upregulated in a large percentage of gastrointestinal lesions and may serve to mediate immuneresponsiveness in certain instances.
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References
O’Callaghan CA, Bell JI, Structure and function of the human MHC class Ib molecules HLA-E, HLA-F and HLA-G. Immunol Rev 1998;163:129–138.
Marin R, Ruiz-Cabello F, Pedrinaci S, et al. Analysis of HLA-E expression in human tumors. Immunogenetics 2003;54:767–775.
Carosella ED, Moreau P, Aractingi S, Rouas-Freiss N. HLA-G: a shield against inflammatory aggression. Trends Immunol 2001;22:553–555.
Amiot L, Onno M, Drenou B, et al. Distribution of HLA-G alternative mRNAs including soluble forms in normal lymphocytes and in lymphoid cell-derived leukemia. Eur J Immunogenet 1996;23:311–320.
Onno M, Guillaudeux T, Amiot L, et al. The HLA-G gene is expressed at a low mRNA level in different human cells and tissues. Hum Immunol 1994;41:79–86.
Singer G, Kurman RJ, McMaster MT, Shih Ie M. HLA-G immunoreactivity is specific for intermediate trophoblast in gestational trophoblastic disease and can serve as a useful marker in differential diagnosis. Am J Surg Pathol 2002;26:914–920.
Urosevic M, Kurrer MO, Kamarashev J, et al. Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production. Am J Pathol 2001;159:817–824.
Pangault C, Amiot L, Caulet-Maugendre S, et al. HLA-G protein expression is not induced during malignant transformation. Tissue Antigens 1999;53:335–346.
Seliger B, Abken H, Ferrone S. HLA-G and MIC expression in tumors and their role in anti-tumor immunity. Trends Immunol 2003;24:82–87.
Urosevic M, Willers J, Mueller B, et al. HLA-G protein up-regulation in primary cutaneous lymphomas is associated with interleukin-10 expression in large cell T-cell lymphomas and indolent B-cell lymphomas. Blood 2002;99:609–617.
Wiendl H, Mitsdoerffer M, Hofmeister V, et al. A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol 2002;168:4772–4780.
Paul P, Cabestre FA, Ibrahim EC, et al. Identification of HLA-G7 as a new splice variant of the HLA-G mRNA and expression of soluble HLA-G5, -G6, and -G7 transcripts in human transfected cells. Hum Immunol 2000;61:1138–1149.
Fournel S, Aguerre-Girr M, Huc X, et al. Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. J Immunol 2000;164:6100–6104.
Riteau B, Rouas-Freiss N, Menier C, et al. HLA-G2,-G3, and -G4 isoforms expressed as nonmature cell surface glycoproteins inhibit NK and antigen-specific CTL cytolysis. J Immunol 2001;166:5018–5026.
Riteau B, Menier C, Khalil-Daher I, et al. HLA-G inhibits the allogeneic proliferative response. J Reprod Immunol 1999;43:203–211.
Bainbridge DR, Ellis SA, Sargent IL. HLA-G suppresses proliferation of CD4(+) T-lymphocytes. J Reprod Immunol 2000;48:17–26.
van Heek NT, Meeker AK, Kern SE, et al. Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am J Pathol 2002;161:1541–1547.
Carosella ED, Paul P, Moreau P, Rouas-Freiss N. HLA-G and HLA-E: fundamental and pathophysiological aspects. Immunol Today 2000;21:532–534.
Contini P, Ghio M, Poggi A, et al. Soluble HL A-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation. Eur J Immunol 2003;33:125–134.
Marchal-Bras-Goncalves R, Rouas-Freiss N, Connan F, et al. Asoluble HLA-G protein that inhibits natural killer cell-mediated cytotoxicity. Transplant Proc 2001;33:2355–2359.
Paul P, Rouas-Freiss N, Khalil-Daher I, et al. HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proc Natl Acad Sci USA 1998;95:4510–4515.
Singer G, Rebmann V, Chen Y-C, et al. HLA-G is potential tumor marker in malignant ascites. Clin Cancer Res 2003;9:4460–4464.
Fukushima Y, Oshika Y, Nakamura M, et al. Increased expression of human histocompatibility leukocyte antigen-G in colorectal cancer cells. Int J Mol Med 1998;2:349–351.
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Hansel, D.E., Rahman, A., Wilentz, R.E. et al. HLA-G upregulation in pre-malignant and malignant lesions of the gastrointestinal tract. Int J Gastrointest Canc 35, 15–23 (2005). https://doi.org/10.1385/IJGC:35:1:015
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DOI: https://doi.org/10.1385/IJGC:35:1:015