Skip to main content
SpringerLink
Log in

Function of HLA-G in cancer immunoediting and its clinical benefits

Fonction de HLA-G dans le cancer immunoediting et ses avantages cliniques

  • Review Article / Article de Synthèse
  • Published:
Journal Africain du Cancer / African Journal of Cancer

Abstract

Human leukocyte antigen G (HLA-G) is a nonclassical major histocompatibility complex (MHC) molecule class I expressed in immune-privileged sites and plays an essential role in the development of maternal tolerance to genetically different fetal tissues. It was described for the first time with its clinical applications by Edgardo D. Carosella and his team at the Saint-Louis Hospital. It is predominantly expressed by the cytotrophoblast, while ectopic expression is observed in certain situations, such as tumor cells. In light of the well documented immunotolerant function of HLA-G, we will focus on the role of this molecule in the escape of tumor cells from different immune cells, its expression in cancers of distinct histology and the use of soluble HLA-G in diagnosis or as pronostic factor in order to detect tumors and to control disease stage, furthermore its use as a novel therapeutic target in cancer.

Résumé

HLA-G est une molécule du complexe majeur d’histocompatibilité (CMH) non classique de classe I exprimée sur des sites immuno-privilégiés et joue un rôle essentiel dans le développement de la tolérance maternelle vis-à-vis des différents tissus foetaux. Elle a été décrite pour la première fois avec ses applications cliniques par Edgardo D. Carosella et son équipe à l’hôpital Saint-Louis. Son expression est prédominante par le cytotrophoblaste, tandis que l’expression ectopique est observée dans certaines situations telles que les cellules tumorales. Compte tenu de la fonction d’immunotolérance de la molécule HLA-G la plus documentée, nous allons nous concentrer sur le rôle de cette molécule dans l’échappement des cellules tumorales aux différentes cellules immunitaires, son expression dans les différents types de cancer et l’utilisation des molécules HLA-G solubles dans le diagnostic ou en tant que facteur pronostique afin de détecter les cellules tumorales et de contrôler le stade de la maladie, par ailleurs son utilisation comme une nouvelle cible thérapeutique dans le cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dunn GP, Bruce AT, Ikeda H, et al (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–8

    Article  CAS  PubMed  Google Scholar 

  2. Smyth MJ, Dunn GP, Schreiber RD (2006) Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90:1–50

    Article  CAS  PubMed  Google Scholar 

  3. Ellis SA, Palmer MS, McMichael AJ (1990) Human trophoblast and the choriocarcinoma cell line BeWo express a truncated HLA Class I molecule. J Immunol 144:731–5

    CAS  PubMed  Google Scholar 

  4. Kovats S, Main EK, Librach C, et al (1990) A class I antigen, HLA-G, expressed in human trophoblasts. Science 248:220–3

    Article  CAS  PubMed  Google Scholar 

  5. Mallet V, Blaschitz A, Crisa L, et al (1999) HLA-G in the human thymus: a subpopulation of medullary epithelial but not CD83(+) dendritic cells expresses HLA-G as a membrane-bound and soluble protein. Int Immunol 11:889–98

    Article  CAS  PubMed  Google Scholar 

  6. Le Discorde M, Moreau P, Sabatier P, et al (2003) Expression of HLA-G in human cornea, an immune-privileged tissue. Hum Immunol 64:1039–44

    Article  PubMed  Google Scholar 

  7. Cirulli V, Zalatan J, McMaster M, et al (2006) The class I HLA repertoire of pancreatic islets comprises the nonclassical class Ib antigen HLA-G. Diabetes 55:1214–22

    Article  CAS  PubMed  Google Scholar 

  8. Menier C, Rabreau M, Challier JC, et al (2004) Erythroblasts secrete the nonclassical HLA-G molecule from primitive to definitive hematopoiesis. Blood 104:3153–60

    Article  CAS  PubMed  Google Scholar 

  9. Paul P, Rouas-Freiss N, Khalil-Daher I, et al (1998) HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proc Natl Acad Sci USA 95:4510–5

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Rouas-Freiss N, Moreau P, Ferrone S, Carosella ED. (2005) HLA-G proteins in cancer: do they provide tumor cells with an escape mechanism? Cancer Res 65:10139–44

    Article  CAS  PubMed  Google Scholar 

  11. Lila N, Carpentier A, Amrein C, et al (2000) Implication of HLA-G molecule in heart-graft acceptance. Lancet 355:2138

    Article  CAS  PubMed  Google Scholar 

  12. Wiendl H, Feger U, Mittelbronn M, et al (2005) Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity. Brain 128:2689–704

    Article  PubMed  Google Scholar 

  13. Aractingi S, Briand N, Le Danff C, et al (2001) HLA-G and NK receptor are expressed in psoriatic skin: a possible pathway for regulating infiltrating T cells? Am J Pathol 159:71–7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Lafon M, Prehaud C, Megret F, et al (2005) Modulation of HLA-G expression in human neural cells after neurotropic viral infections. J Virol 79:15226–37

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Carosella ED, Moreau P, Le Maoult J, et al (2003) HLA- G molecules: from maternal-fetal tolerance to tissue acceptance. Adv Immunol 81:199–252

    Article  CAS  PubMed  Google Scholar 

  16. Park GM, Lee S, Park B, et al (2004) Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis. Biochem Biophys Res Commun 313:606–11

    Article  CAS  PubMed  Google Scholar 

  17. Colonna M, Navarro F, Bellon T, et al (1997) A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J Exp Med 186:1809–18

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Colonna M, Samaridis J, Cella M, et al (1998) Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J Immunol 60:3096–100

    Google Scholar 

  19. Rajagopalan S, Long EO (1999) A human histocompatibility leukocyte antigen (HLA)-G specific receptor expressed on all natural killer cells. J Exp Med 189:1093–10

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Dietrich J, Cella M, Colonna M (2001) Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization. J Immunol 166:2514–21

    Article  CAS  PubMed  Google Scholar 

  21. Apps R, Gardner L, Sharkey AM, et al (2007) A homodimeric complex of HLA-G on normal trophoblast cells modulates antigen-presenting cells via LILRB1. Eur J Immunol 37:1924–37

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Gonen-Gross T, Achdout H, Gazit R, et al (2003) Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function. J Immunol 171:1343–51

    Article  CAS  PubMed  Google Scholar 

  23. Shiroishi M, Kuroki K, Ose T, et al (2006) Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer. J Biol Chem 281:10439–47

    Article  CAS  PubMed  Google Scholar 

  24. Fons P, Chabot S, Cartwright JE, Lenfant F, et al (2006) Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells. Blood 108:2608–15

    Article  CAS  PubMed  Google Scholar 

  25. Riteau B, Menier C, Khalil-Daher I, Martinozzi S (2001) HLA-G1 co-expression boosts the HLA class I-mediated NK lysis inhibition. Int Immunol 13:193–201

    Article  CAS  PubMed  Google Scholar 

  26. LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED (2004) HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+ T cells. Proc Natl Acad Sci USA 101:7064–9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Contini P, Ghio M, Poggi A, et al (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 33:125–34

    Article  CAS  PubMed  Google Scholar 

  28. Caumartin J, Favier B, Daouya M, et al (2007) Trogocytosis-based generation of suppressive NK cells. EMBO J 26:1423–33

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. LeMaoult J, Caumartin J, Daouya M, et al (2007) Immune regulation by pretenders: cell-to-cell transfers of HLA-G make effector T cells act as regulatory cells. Blood 109:2040–8

    Article  CAS  PubMed  Google Scholar 

  30. Urosevic M, Dummer R (2008) Human leukocyte antigen-G and cancer immunoediting. Cancer Res 68:627–30

    Article  CAS  PubMed  Google Scholar 

  31. Rouas-Freiss N, Marchal RE, Kirszenbaum M, et al (1997) The alpha1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: is HLA-G the public ligand for natural killer cell inhibitory receptors? Proc Natl Acad Sci USA 94:5249–5

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Bainbridge DR, Ellis SA, Sargent IL (2000) HLA-G suppresses proliferation of CD4(+) T-lymphocytes. J Reprod Immunol 48:17–26

    Article  CAS  PubMed  Google Scholar 

  33. Khalil-Daher I, Riteau B, Menier C, et al (1999) Role of HLA-G versus HLA-E on NK function: HLA-G is able to inhibit NK cytolysis by itself. J Reprod Immunol 43:175–82

    Article  CAS  PubMed  Google Scholar 

  34. LeMaoult J, Zafaranloo K, Le Danff C, Carosella ED (2005) HLA-G up-regulates ILT2, ILT3, ILT4, and KIR2DL4 in antigen presenting cells, NK cells, and T cells. FASEB J 19:662–4

    CAS  PubMed  Google Scholar 

  35. Polakova K, Krcova M, Kuba D, Russ G (2003) Analysis of HLA-G expression in malignant hematopoietic cells from leukemia patients. Leuk Res 27:643–8

    Article  CAS  PubMed  Google Scholar 

  36. Yan WH, Lin A, Chen BG, et al (2008) Unfavourable clinical implications for HLA-G expression in acute myeloid leukaemia. J Cell Mol Med 12:889–98

    Article  PubMed Central  PubMed  Google Scholar 

  37. Gros F, Sebti Y, de Guibert S, et al (2006) Soluble HLA-G molecules increase during acute leukemia, especially in subtypes affecting monocytic and lymphoid lineages. Neoplasia 8:223–30

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Leleu X, Le Friec G, Facon T, et al (2005) Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance. Clin Cancer Res 11:7297–303

    Article  CAS  PubMed  Google Scholar 

  39. Polakova K, Zeleznikova T, Russ G (2013) HLA-G5 in the blood of leukemia patients and healthy individuals. Leuk Res 37:139–45

    Article  CAS  PubMed  Google Scholar 

  40. Hurks HM, Valter MM, Wilson L, et al (2001) Uveal melanoma: no expression of HLA-G. Invest Ophthalmol Vis Sci 42:3081–4

    CAS  PubMed  Google Scholar 

  41. Rouas-Freiss N, Moreau P, Ferrone S, Carosella ED (2005) HLA-G proteins in cancer: do they provide tumor cells with an escape mechanism? Cancer Res 65:10139–44

    Article  CAS  PubMed  Google Scholar 

  42. Riteau B, Faure F, Menier C, et al (2003) Exosomes bearing HLA-G are released by melanoma cells. Hum Immunol 64:1064–72

    Article  CAS  PubMed  Google Scholar 

  43. Singer G, Rebmann V, Chen YC, et al (2003) HLA-G is a potential tumor marker in malignant ascites. Clin Cancer Res 9:4460–4

    CAS  PubMed  Google Scholar 

  44. Zhu CB, Wang CX, Zhang X, et al (2011) Serum sHLA-G levels: a useful indicator in distinguishing colorectal cancer from benign colorectal diseases. Int J Cancer 28:617–22

    Article  Google Scholar 

  45. Zheng N, Wang CX, Zhang X, et al (2011) Up-regulation of HLA-G expression in cervical premalignant and malignant lesions. Tissue Antigens 77:218–24

    Article  CAS  PubMed  Google Scholar 

  46. Frumento G, Franchello S, Palmisano GL, et al (2000) Melanomas and melanoma cell lines do not express HLA-G, and the expression cannot be induced by gamma IFN treatment. Tissue Antigens 56:30–7

    Article  CAS  PubMed  Google Scholar 

  47. El-Chennawi FA, Auf FA, El-Diasty AM, et al (2005) Expression of HLA-G in cancer bladder. Egypt J Immunol 12:57–64

    PubMed  Google Scholar 

  48. Li BL, Lin A, Zhang XJ, et al (2009) Characterization of HLA-G expression in renal cell carcinoma. Tissue Antigens 74:213–21

    Article  CAS  PubMed  Google Scholar 

  49. Langat DK, Sue Platt J, Tawfik O, et al (2006) Differential expression of human leukocyte antigen-G (HLA-G) messenger RNAs and proteins in normal human prostate and prostatic adenocarcinoma. J Reprod Immunol; 71:75–86

    Article  CAS  PubMed  Google Scholar 

  50. Wang Y, Ye Z, Meng XQ, Zheng SS (2011) Expression of HLA-G in patients with hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 10:158–63

    Article  CAS  PubMed  Google Scholar 

  51. Yie SM, Yang H, Ye SR, et al (2007) Expression of human leukocyte antigen G (HLA-G) correlates with poor prognosis in gastric carcinoma. Ann Surg Oncol 14:2721–9

    Article  PubMed  Google Scholar 

  52. Ishigami S, Natsugoe S, Miyazono F, et al (2006) HLA-G expression in gastric cancer. Anticancer Res 26:2467–72

    CAS  PubMed  Google Scholar 

  53. Ye SR, Yang H, Li K, et al (2007) Human leukocyte antigen G expression: as a significant prognostic indicator for patients with colorectal cancer. Mod Pathol 20:375–83

    Article  CAS  PubMed  Google Scholar 

  54. Fukushima Y, Oshika Y, Nakamura M, et al (1998) Increased expression of human histocompatibility leukocyte antigen-G in colorectal cancer cells. Int J Mol Med 2:349–51

    CAS  PubMed  Google Scholar 

  55. Jiang XP, Phillips JT, Barnett BG, Head JF (2011) Human leukocyte antigen G expression in breast cancer: role in immunosuppression. Cancer Biother Radiopharm 26:153–7

    Article  PubMed  Google Scholar 

  56. He X, Dong DD, Yie SM, et al (2010) HLA-G expression in human breast cancer: implications for diagnosis and prognosis, and effect on allocytotoxic lymphocyte response after hormone treatment in vitro. Ann Surg Oncol 17:1459–69

    Article  PubMed  Google Scholar 

  57. Provatopoulou X, Kalogera E, Sagkriotis A, et al (2012) Soluble human leukocyte antigen-G expression in patients with ductal and lobular breast malignancy. Anticancer Res 32:1021–6

    CAS  PubMed  Google Scholar 

  58. Lin A, Yan WH, Xu HH, Gan MF, et al (2007) HLA-G expression in human ovarian carcinoma counteracts NK cell function. Ann Oncol 18:1804–9

    Article  CAS  PubMed  Google Scholar 

  59. Li XJ, Zhang X, Lin A, Ruan YY, et al (2012) Human leukocyte antigen-G (HLA-G) expression in cervical cancer lesions is associated with disease progression. Hum Immunol 73:946–9

    Article  CAS  PubMed  Google Scholar 

  60. Menier C, Rouas-Freiss N, Carosella E.D (2009) The HLA-G non classical MHC class I molecule is expressed in cancer with poor prognosis. Implications in tumour escape from immune system and clinical applications. Atlas Genet Cytogenet Oncol Haematol 13:531–42

    Google Scholar 

  61. Carosella ED, Dausset J, Rouas-Freiss N (1999) Immunotolerant functions of HLA-G. Cell Mol Life Sci 55:327–33

    Article  CAS  PubMed  Google Scholar 

  62. Yie SM (2012) HLA-G (major histocompatibility complex, class I, G). Atlas Genet Cytogenet Oncol Haematol 16:403–11

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratoire de Génie microbiologique et application, Equipe : Biologie Physiologie Cellulaire et Moléculaire, Département de Biologie Animale, Faculté des Sciences de la Nature et de la Vie, Université Constantine 1, Ain Elbey, 25017, Constantine, Algérie

    O. Oucherif & D. Naimi

Authors
  1. O. Oucherif
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Naimi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O. Oucherif.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oucherif, O., Naimi, D. Function of HLA-G in cancer immunoediting and its clinical benefits. J Afr Cancer 7, 132–139 (2015). https://doi.org/10.1007/s12558-015-0361-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12558-015-0361-6

Keywords

Mots clés

Search

Navigation