Abstract
To analyze expression of human leukocyte antigen-G (HLA-G) in gastric adenocarcinoma and correlate its expression with histological and clinical variables. A continuous series of 94 unselected patients with gastric adenocarcinoma (stage I to III) were selected. All histological and clinical variables were collected including the intensity of intra- and peri-tumor lymphocytic infiltration. HLA-G expression was investigated using immunohistochemistry. All histological samples analyzed for HLA-G expression were taken from the primary gastric lesion and included non-neoplastic mucosa. Evaluation of HLA-G expression was performed on the transition zone between tumor and non-neoplastic mucosa, and the invasive front of the tumor and assessment was performed as follows: percentage of positive (strong expression vs weak) cells. A variable amount of HLA-G-positive tumor cells was found in 24 out of 94 cases (25.5%). No significant correlation was found between HLA-G expression and other clinicopathological variables (sex, age, stage, grade, histotype). The overall median survival was worse in patients with HLA-G-positive adenocarcinoma (24.3 months, CI95% 7.7–41.0) compared to those with HLA-G-negative tumors (66.3 months, CI95% 53.0–79.7; p < 0.0001). Two- and 5-year survival rates of HLA-G-negative patients were 88 and 44%, respectively, while were 42 and 11% in those HLA-G-positive. This trend was observed in all stages but was more marked in stage III. HLA-G expression is associated with poor survival in stage III gastric cancer patients and represents a possible immunoescape mechanism of cancer cells.
Similar content being viewed by others
References
Contini P, Ghio M, Poggi A, Filaci G, Indiveri F, Ferrone S, Puppo F (2003) Soluble HLA-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 33:125–134
Ploegh HL, Orr HT, Strominger JL (1981) Major histocompatibility antigens: the human (HLA-A, -B, -C) and murine (H-2K, H-2D) class I molecules. Cell 24:287–299
O’Callaghan CA, Bell JL (1998) Structure and function of the human MHC class Ib molecules HLA-E, HLA-F and HLA-G. Immunol Rev 163:129–138
Pistoia V, Morandi F, Wang X, Ferrone S (2007) Soluble HLA-G. Are they clinically relevant? Semin Cancer Biol 17:469–479
Feger U, Tolosa E, Huang YH, Waschbisch A, Biedermann T, Melms A, Wiendl H (2007) HLA-G expression defines a novel regulatory T-cell subset present in human peripheral blood and sites of inflammation. Blood 110:568–577
Rizzo R, Mapp CE, Melchiorri L, Maestrelli P, Visentin A, Ferretti S, Bononi I, Miotto D, Baricordi OR (2005) Defective production of soluble HLA-G molecules by peripheral blood monocytes in patients with asthma. J Allergy Clin Immunol 115:508–513
Bainbridge DR, Ellis SA, Sargent IL (2000) HLA-G suppresses proliferation of CD4 (+) T-lymphocytes. J Reprod Immunol 48:17–26
Lila N, Rouas-Freiss N, Dausset J, Carpentier A, Carosella ED (2001) Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci U S A 98:12150–12155
Le Gal FA, Riteau B, Sedlik C, Khalil-Daher I, Menier C, Dausset J, Guillet JG, Carosella ED, Rouas-Freiss N (1999) HLA-G-mediated inhibition of antigen-specific cytotoxic T lymphocytes. Int Immunol 11:1351–1356
Riteau B, Menier C, Khalil-Daher I, Martinozzi S, Pla M, Dausset J, Carosella ED, Rouas-Freiss N (2001) HLA-G1 coexpression boosts the HLA class I-mediated NK lysis inhibition. Int Immunol 13:193–201
Carosella ED, Favier B, Rouas-Freiss N, Moreau P, Lemaoult J (2008) Beyond the increasing complexity of the immunomodulatory HLA-G molecule. Blood 111:4862–4870
Amiot L, Ferrone S, Grosse-Wilde H, Seliger B (2011) Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention? Cell Mol Life Sci 68(3):417–431
LeMaoult J, Le Discorde M, Rouas-Freiss N, Moreau P, Menier C, McCluskey J, Carosella ED (2003) Biology and functions of human leukocyte antigen-G in health and sickness. Tissue Antigens 62:273–284
Rebmann V, Regel J, Stolke D, Grosse-Wilde H (2003) Secretion of sHLA-G molecules in malignancies. Semin Cancer Biol 13:371–377
Sebti Y, Le Friec G, Pangault C, Gros F, Drénou B, Guilloux V, Bernard M, Lamy T, Fauchet R, Amiot L (2003) Soluble HLA-G molecules are increased in lymphoproliferative disorders. Hum Immunol 64:1093–1101
Nückel H, Rebmann V, Dürig J, Dührsen U, Grosse-Wilde H (2005) HLA-G expression is associated with an unfavorable outcome and immunodeficiency in chronic lymphocytic leukemia. Blood 105:1694–1698
Ugurel S, Rebmann V, Ferrone S, Tilgen W, Grosse-Wilde H, Reinhold U (2001) Soluble human leukocyte antigen-G serum level is elevated in melanoma patients and is further increased by interferon-alpha immunotherapy. Cancer 92:369–376
Singer G, Rebmann V, Chen YC, Liu HT, Ali SZ, Reinsberg J, McMaster MT, Pfeiffer K, Chan DW, Wardelmann E, Grosse-Wilde H, Cheng CC, Kurman RJ, IeM S (2003) HLA-G is a potential tumor marker in malignant ascites. Clin Cancer Res 9:4460–4464
Lefebvre S, Antoine M, Uzan S, McMaster M, Dausset J, Carosella ED, Paul P (2002) Specific activation of the non-classical class I histocompatibility HLA-G antigen and expression of the ILT2 inhibitory receptor in human breast cancer. J Pathol 196:266–274
Urosevic M, Kurrer MO, Kamarashev J, Mueller B, Weder W, Burg G, Stahel RA, Dummer R, Trojan A (2001) Human leukocyte antigen G up-regulation in lung cancer associates with high-grade human histology, leukocyte antigen class I loss and interleukin-10 production. Am J Pathol 159:817–824
Barrier BF, Kendall BS, Sharpe-Timms KL, Kost ER (2006) Characterization of human leukocyte antigen-G (HLA-G) expression in endometrial adenocarcinoma. Gynecol Oncol 103:25–30
Downs-Kelly E, Schade AE, Hansel DE (2007) The role of HLA-G in gastrointestinal inflammatory disease and malignancy. Semin Cancer Biol 17(6):451–458
Ishigami S, Natsugoe S, Miyazono F, Nakajo A, Tokuda K, Matsumoto M, Okumura H, Douchi T, Hokita S, Aikou T (2006) HLA-G expression in gastric cancer. Anticancer Res 26(3B):2467–2472
Yie M, Yang H, Ye SR, Li K, Dong DD, Lin XM (2007) Expression of human leukocyte antigen G (HLA-G) correlates with poor prognosis in gastric carcinoma. Ann Surg Oncol 14(10):2721–2729
Du L, Xiao X, Wang C, Zhang X, Zheng N, Wang L, Zhang X, Li W, Wang S, Dong Z (2011) Human leukocyte antigen-G is closely associated with tumor immune escape in gastric cancer by increasing local regulatory T cells. Cancer Sci 102(7):1272–1280
Tuncel T, Karagoz B, Haholu A, Ozgun A, Emirzeoglu L, Bilgi O, Kandemir EG (2013) Immunoregulatory function of HLA-G in gastric cancer. Asian Pac J Cancer Prev 14(12):7681–7684
Bosman FT, Carneiro F, Hruban RH, Teise ND (2010) Tumours of the stomach. In: Bosman FT, Carneiro F, Hruban RH, Teise ND (eds) WHO Classification of Tumours of the Digestive System, 4th edn. IARC Publisher, Lyon, pp 45–80
Lauren P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma: an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49
Ming SC (1977) Gastric carcinoma: a pathobiological classification. Cancer 39:2475–2485
Rouas-Freiss N, Goncalves RM, Menier C, Dausset J, Carosella ED (1997) Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc Natl Acad Sci U S A 94:11520–115205
Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–1193
Carosella ED, Moreau P, Lemaoult J, Rouas-Freiss N (2008) HLA-G: from biology to clinical benefits. Trends Immunol 29:125–132
Grillo F, Fassan M, Ceccaroli C, Giacometti C, Curto M, Zagonel V, Ceppa P, Nitti D, Castoro C, Fiocca R, Rugge M, Mastracci L (2013) The reliability of endoscopic biopsies in assessing HER2 status in gastric and gastroesophageal junction cancer: a study comparing biopsies with surgical samples. Transl Oncol 6:10–16
Cho J, Lee J, Bang H, Kim ST, Park SH, An JY, Choi MG, Lee JH, Sohn TS, Bae JM, Kang WK, Kim S, Kim KM (2017) Programmed cell death-ligand 1 expression predicts survival in patients with gastric carcinoma with microsatellite instability. Oncotarget 8:13320–13328
Rouas-Freiss N, Moreau P, Menier C, Carosella ED (2003) HLA-G in cancer: a way to turn off the immune system. Semin Cancer Biol 13(5):325–336
Yie SM, Yang H, Ye SR, Li K, Dong DD, Lin XM (2007) Expression of human leucocyte antigen G (HLA-G) is associated with prognosis in non-small cell lung cancer. Lung Cancer 58(2):267–274
Swets M, König MH, Zaalberg A, Dekker-Ensink NG, Gelderblom H, van de Velde CJ, van den Elsen PJ, Kuppen PJ (2016) HLA-G and classical HLA class I expression in primary colorectal cancer and associated liver metastases. Hum Immunol 77(9):773–779
Morandi F, Rizzo R, Fainardi E, Rouas-Freiss N, Pistoia V (2016) Recent advances in our understanding of HLA-G biology: lessons from a wide spectrum of human diseases. J Immunol Res 2016:4326495
Rouas-Freiss N, Moreau P, LeMaoult J, Carosella ED (2014) The dual role of HLA-G in cancer. J Immunol Res 2014:359748
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Human rights statement and informed consent
All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. This analysis was approved by the Ethics Committees at the Ospedale Policlinico San Martino.
Additional information
Guidelines of the STROBE statement have been adopted.
Rights and permissions
About this article
Cite this article
Murdaca, G., Calamaro, P., Lantieri, F. et al. HLA-G expression in gastric carcinoma: clinicopathological correlations and prognostic impact. Virchows Arch 473, 425–433 (2018). https://doi.org/10.1007/s00428-018-2379-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-018-2379-0