Immunogenetics

, Volume 65, Issue 5, pp 333–343

KIR gene variability in cutaneous malignant melanoma: influence of KIR2D/HLA-C pairings on disease susceptibility and prognosis

  • José A. Campillo
  • Isabel Legaz
  • M. Rocío López-Álvarez
  • José Miguel Bolarín
  • Beatriz Las Heras
  • Manuel Muro
  • Alfredo Minguela
  • María R. Moya-Quiles
  • Rosa Blanco-García
  • Helios Martínez-Banaclocha
  • Ana M. García-Alonso
  • M. Rocío Álvarez-López
  • Jorge A. Martínez-Escribano
Original Paper

Abstract

Natural killer and CD8+ T cells are believed to be involved in the immune protection against melanoma. Their function may be regulated by a group of receptors defined as killer immunoglobulin-like receptors (KIRs) and their cognate HLA class I ligands. In this study, we analyzed the influence of KIR genes and KIR/HLA-I combinations on melanoma susceptibility and/or prognosis in a Spanish Caucasian population. For this purpose, KIR genotyping by PCR-SSP and HLA-C genotyping by reverse PCR-SSO were performed in 187 melanoma patients and 200 matched controls. We found a significantly low frequency of KIR2DL3 in nodular melanoma (NM) patients (P = 0.001) and in ulcerated melanoma patients (P < 0.0001). Similarly, the KIR2DL3/C1 combination was significantly decreased in melanoma patients (Pc = 0.008) and in patients with sentinel lymph node (SLN) melanoma metastasis (Pc = 0.002). Multivariate logistic regression models showed that KIR2DL3 behaves as a protective marker for NM and ulcerated melanoma (P = 0.02, odds ratio (OR) = 0.14 and P = 0.04, OR = 0.28, respectively), whereas the KIR2DL3/C1 pair acts as a protective marker for melanoma (P = 0.017, OR = 0.54), particularly superficial spreading melanoma (P = 0.02, OR = 0.52), and SLN metastasis (P = 0.0004, OR = 0.14). In contrast, the KIR2DL3(−)/C1C2 genotype seems to be correlated with NM and ulceration. We also report that the KIR2DL1(+)/S1(−)/C2C2 genotype is associated with susceptibility to melanoma and SLN metastasis. Altogether, the study of KIR2D genes and HLA-C ligands may help in assessing cutaneous melanoma risk and prognosis.

Keywords

Melanoma KIR receptors HLA class I ligands Sentinel lymph node metastasis Ulceration 

References

  1. Al Omar S, Middleton D, Marshall E, Porter D, Xinarianos G, Raji O, Field JK, Christmas SE (2010) Associations between genes for killer immunoglobulin-like receptors and their ligands in patients with solid tumors. Human Immunol 71:976–981CrossRefGoogle Scholar
  2. Anichini A, Vegetti C, Mortarini R (2004) The paradox of T cell mediated antitumor immunity in spite of poor clinical outcome in human melanoma. Cancer Immunol Immunother 53:855–864PubMedCrossRefGoogle Scholar
  3. Aranda-Romo S, García-Sepulveda CA, Comas-García A, Lovato-Salas F, Salgado-Bustamante M, Gómez-Gómez A, Noyola DE (2012) Killer-cell immunoglobulin-like receptors (KIR) in severe A (H1N1) 2009 influenza infections. Immunogenetics 64:653–662PubMedCrossRefGoogle Scholar
  4. Bakker AB, Phillips JH, Figdor CG, Lanier LL (1998) Killer cell inhibitory receptors for MHC class I molecules regulate lysis of melanoma cells mediated by NK cells, γδ T cells, and antigen-specific CTL. J Immunol 160:5239–5245PubMedGoogle Scholar
  5. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, Sondak VK (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199–6206PubMedCrossRefGoogle Scholar
  6. Bashirova AA, Martin MP, McVicar DW, Carrington M (2006) The killer immunoglobulin like receptor gene cluster: tuning the genome for defense. Annu Rev Genomics Hum Genet 7:277–300PubMedCrossRefGoogle Scholar
  7. Campillo JA, Martínez-Escribano JA, Muro M, Moya-Quiles R, Marín LA, Montes-Ares O, Guerra N, Sánchez-Pedreño P, Frías JF, Lozano JA, García-Alonso AM, Álvarez-López MR (2006a) HLA class I and class II frequencies in patients with cutaneous malignant melanoma from south-eastern Spain: the role of HLA-C in disease prognosis. Immunogenetics 57:926–933PubMedCrossRefGoogle Scholar
  8. Campillo JA, Martínez-Escribano JA, Moya-Quiles MR, Marín LA, Muro M, Guerra N, Parrado A, Campos M, Frías JF, Minguela A, García-Alonso AM, Álvarez-López MR (2006b) Natural killer receptors on CD8 T cells and Naural Killer cells from different HLA-C phenotypes in melanoma patients. Clin Cancer Res 12:4822–4831PubMedCrossRefGoogle Scholar
  9. Carrega P, Pezzino G, Queirolo P, Bonaccorsi I, Falco M, Vita G, Pende D, Misefari A, Moretta A, Mingari MC, Moretta L, Ferlazzo G (2009) Susceptibility of human melanoma cells to autologous natural killer (NK) cell killing: HLA-related effector mechanisms and role of unlicensed NK cells. PLoS One 4:e8132PubMedCrossRefGoogle Scholar
  10. Casado JG, Soto R, De la Rosa O, Peralbo E, del Carmen M-VM, Rioja L, Peña J, Solana R, Tarazona R (2005) CD8 T-cells expressing NK associated receptors are increased in melanoma patients and display an effector phenotype. Cancer Immunol Immunother 54:1162–1171PubMedCrossRefGoogle Scholar
  11. Casado JG, Pawelec G, Morgado S, Sanchez-Correa B, Delgado E, Gayoso I, Duran E, Solana R, Tarazona R (2009) Expression of adhesion molecules and ligands for activating and costimulatory receptors involved in cell-mediated cytotoxicity in a large panel of human melanoma cell lines. Cancer Immunol Immunother 58:1517–1526PubMedCrossRefGoogle Scholar
  12. Chewning JH, Gudme CN, Hsu KC, Selvakumar A, Dupont B (2007) KIR2DS1-positive NK cells mediate alloresponse against the C2 HLA-KIR ligand group in vitro. J Immunol 179:854–868PubMedGoogle Scholar
  13. Chouaib S, Thiery J, Gati A, Gerra N, El Behi M, Dorothée G, Mami-Chouaib F, Bellet B, Caignard A (2002) Tumor escape from killing: Role of killer inhibitory receptors and acquisition of tumor resistance to cell death. Tissue Antigens 60:273–281PubMedCrossRefGoogle Scholar
  14. Cochran AJ, Huang R-R, Lee J, Itakura E, Leong SP, Essner R (2006) Tumour induced immune modulation of sentinel lymph nodes. Nat Rev Immunol 6:659–670PubMedCrossRefGoogle Scholar
  15. Cognet C, Farnarier C, Gauthier, Frassati C, André P, Magérus-Chatinet A, Anfossi N, Rieux-Laucat F, Vivier E, Schleinitz N (2010) Expression of the HLA-C2-specific activating killer-cell Ig-like receptor KIR2DS1 on NK and T cells. Clin Immunol 135:26–32PubMedCrossRefGoogle Scholar
  16. Du Z, Gjertson DW, Reed EF, Rajalingam R (2007) Receptor-ligand analyses define minimal killer cell Ig-like receptor (KIR) in humans. Immunogenetics 59:1–15PubMedCrossRefGoogle Scholar
  17. Fauriat C, Ivarsson MA, Ljunggren H-G, Malmberg K-J, Michaëlsson J (2010) Education of human natural killer cells by activating killer cell immunoglobulin-like receptors. Blood 115:1166–1174PubMedCrossRefGoogle Scholar
  18. Foley BA, De Santis D, Van Beelen E, Lathbury LJ, Christiansen FT, Witt CS (2008) The reactivity of Bw4+ HLA-B and HLA-A alleles with KIR3DL1: implications for patient and donor suitability for haploidentical stem cell transplantations. Blood 112:435–443PubMedCrossRefGoogle Scholar
  19. Garrido F, Ruiz-Cabello F, Cabrera T, Perez-Villar JJ, Lopez-Botet M, Duggan-Keen M, Stern PL (1997) Implications for immunosurveillance of altered HLA class I phenotypes in human tumors. Immunol Today 18:89–95PubMedCrossRefGoogle Scholar
  20. Graef T, Moesta AK, Norman PJ, Abi-Rached L, Vago L, Older Aguilar AM, Gleimer M, Hammond JA, Guethlein LA, Bushnell DA, Robinson PJ, Parham P (2009) KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C. J Exp Med 206:2557–2572PubMedCrossRefGoogle Scholar
  21. Hansasuta P, Dong T, Thananchai H, Weekes M, Willber C, Aldemir H, Rowland-Jones S, Braud VM (2004) Recognition of HLA-A3 and HLA-11 by KIR3DL2 is peptide-specific. Eur J Immunol 34:1673–1679PubMedCrossRefGoogle Scholar
  22. Hollenbach JA, Nocedal I, Ladner MB, Single RM, Trachtenberg EA (2012) Killer cell immunoglobulin-like receptor (KIR) gene content variation in the HGDP-CEPH populations. Immunogenetics 64:719–737PubMedCrossRefGoogle Scholar
  23. Katz G, Gazit R, Arnon TI, Gonen-Gross T, Tarcic G, Markel G, Gruda R, Achdout H, Drize O, Merims S, Mandelboim O (2004) MHC class I-independent recognition of NK-activating receptor KIR2DS4. J Immunol 173:1819–1825PubMedGoogle Scholar
  24. Knapp S, Warshow U, Hegazy D, Brackenbury L, Guha IN, Fowell A, Little AM, Alexander GJ, Rosenberg WM, Cramp ME, Khakoo SI (2010) Consistent beneficial effects of killer cell immunoglobulin-like receptor 2DL3 and group 1 human leukocyte antigen-C following exposure to hepatitis C virus. Hepatology 51:1168–1175PubMedCrossRefGoogle Scholar
  25. Konjevic G, Mirjacic Martinovic K, Jurisic V, Babovic N, Spuzic I (2009) Biomarkers of suppressed natural killer (NK) cell function in metastatic melanoma: decreased NKG2D and increased CD158a receptors on CD3-CD16+ NK cells. Biormarkers 14:258–270CrossRefGoogle Scholar
  26. Larrieu P, Renaud V, Godet Y, Jotereau F, Fonteneau JF (2008) A HLA-Cw*0701 restricted melan-A/MART1 epitope presented by melanoma tumor cells to CD8+ tumor infiltrating lymphocytes. Cancer Immunol Immunother 57:745–752PubMedCrossRefGoogle Scholar
  27. Lee PP, Yee C, Savage PA, Fong L, Brokstedt D, Weber J, Johnson D, Swetter S, Thompson J, Greenberg PD, Roederer M, Davis MM (1999) Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 5:677–685PubMedCrossRefGoogle Scholar
  28. Maat W, Van der Slik AR, Verhoeven DH, Alizadeh DZ, Ly LV, Verduijn W, Luyten GP, Mulder A, van Hall T, Koning F, Jager MJ, van Bergen J (2009) Evidence for Natural killer cell-mediated protection from metastasis formation in uveal melanoma patients. Investig Ophthalmol Vis Sci 50:2888–2895CrossRefGoogle Scholar
  29. Mandelboim O, Reyburn HT, Valés-Gómez M, Pazmany L, Colonna M, Borsellino G, Strominger JL (1996) Protection from lysis by Natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules. J Exp Med 184:913–922PubMedCrossRefGoogle Scholar
  30. Martayan A, Fraioli R, Giorda E, Setini A, Ciccarelli G, Delfino L, Ferrara GB, Giacomini P (1999) Biosynthesis of HLA-C heavy chains in melanoma cells with multiple defects in the expression of HLA-A, -B, -C molecules. Br J Cancer 80:639–649PubMedCrossRefGoogle Scholar
  31. Martin MP, Borecki IB, Zhang Z, Nguyen L, Ma D, Gao X, Qi Y, Carrington M, Rader JS (2010) HLA-Cw group 1 ligands for KIR increase susceptibility to invasive cervical cancer. Immunogenetics 62:761–765PubMedCrossRefGoogle Scholar
  32. Middleton D, Gonzelez F (2010) The extensive polymorphism of KIR genes. Immunology 129:8–19PubMedCrossRefGoogle Scholar
  33. Moesta AK, Norman PJ, Yawata M, Yawata N, Gleimer M, Parham P (2008) Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3. J Immunol 180:3969–3979PubMedGoogle Scholar
  34. Moreta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L (2001) Activating receptors and co-receptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19:197–223CrossRefGoogle Scholar
  35. Moretta L, Bottino C, Pende D, Castriconi R, Mingari MC, Moretta A (2006) Surface NK receptors and their ligands on tumor cells. Semin Immunol 18:151–158PubMedCrossRefGoogle Scholar
  36. Nasca R, Carbone E (1999) Natural killer cells as potential tools in melanoma metastatic spread control. Oncol Res 11:339–343PubMedGoogle Scholar
  37. Naumova E, Mihaylova A, Milena I, Mihailova S (2007) Impact of KIR/HLA ligand combinations on immune responses in malignant melanoma. Cancer Immunol Immunother 56:95–100PubMedCrossRefGoogle Scholar
  38. Naumova E, Mihaylova A, Stoitchkov K, Ivanova M, Quin L, Toneva M (2005) Genetic polymorphism of NK receptors and their ligands in melanoma patients: prevalence of inhibitory over activating signals. Cancer Immunol Immunother 54:172–178PubMedCrossRefGoogle Scholar
  39. Parham P (2004) NK cells lose their inhibition. Science 305:786–787PubMedCrossRefGoogle Scholar
  40. Parham P (2005) MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 5:201–214PubMedCrossRefGoogle Scholar
  41. Pende D, Accame L, Pareti L, Mazzocchi A, Moretta A, Parmiani G, Moretta L (1998) The susceptibility to natural killer cell-mediated lysis of HLA class-I positive melanomas reflects the expression of insufficient amounts of different HLA class I alleles. Eur J Immunol 28:2384–2394PubMedCrossRefGoogle Scholar
  42. Pende D, Marcenaro S, Falco M, Martini S, Bernardo ME, Montagna D, Romeo E, Cognet C, Martinetti M, Maccario R, Mingari MC, Vivier E, Moretta L, Locatelli F, Moretta A (2009) Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity. Blood 113:3119–3129PubMedCrossRefGoogle Scholar
  43. Remtoula N, Bensussan A, Marie-Cardine A (2008) Cutting Edge: Selective expression of inhibitory or activating killer cell Ig-like receptors in circulating CD4+ T lymphocytes. J Immunol 180:2767–2771PubMedGoogle Scholar
  44. Tajik N, Shahsavar F, Poormoghim H, Radjabzadeh MF, Mousavi T, Jalali A (2011) KIR3DL1 + HLA-B Bw4Ile80 and KIR2DS1 + HLA-C2 combinations are both associated with ankylosing spondylitis in the Iranian population. Int J Immunogenet 38:403–409PubMedCrossRefGoogle Scholar
  45. Thielens A, Vivier E, Romagné F (2012) NK cells MHC class I specific receptors (KIR) from biology to clinical intervention. Curr Opin Immunol 24:239–245PubMedCrossRefGoogle Scholar
  46. Tiwari JL, Terasaki PI (1985) The data and statistical analysis. In: Tiwary JL, Terasaki PI (eds) HLA and disease associations. Springer, New York, p 18CrossRefGoogle Scholar
  47. Venstrom JM, Pittari G, Gooley TA, Chewning JH, Spellman S, Haagenson M, Gallagher MM, Malkki M, Petersdorf E, Dupont B, Hsu KC (2012) HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med 367:805–816PubMedCrossRefGoogle Scholar
  48. Verheyden S, Ferrone S, Mulder A, Claas FH, Schots R, De Moerloose B, Benoit Y, Demanet C (2009) Role of the inhibitory KIR ligand HLA-Bw4 and HLA-C expression levels in the recognition of leukemic cells by natural killer cells. Cancer Immunol Immunother 58:855–865PubMedCrossRefGoogle Scholar
  49. Vilches C, Castaño J, Gómez-Lozano N, Estefania E (2007) Facilitation of KIR genotyping by a PCR-SSP method that amplifies short DNA fragments. Tissue Antigens 70:415–422PubMedCrossRefGoogle Scholar
  50. Warycha MA, Christos PJ, Mazumdar M, Darvishian F, Shapiro RL, Berman RS, Pavlick AC, Kopf AW, Polsky D, Osman I (2008) Changes in the presentation of nodular and superficial spreading melanomas over 35 years. Cancer 113:3341–3348PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • José A. Campillo
    • 1
  • Isabel Legaz
    • 1
  • M. Rocío López-Álvarez
    • 1
  • José Miguel Bolarín
    • 1
  • Beatriz Las Heras
    • 1
  • Manuel Muro
    • 1
  • Alfredo Minguela
    • 1
  • María R. Moya-Quiles
    • 1
  • Rosa Blanco-García
    • 1
  • Helios Martínez-Banaclocha
    • 1
  • Ana M. García-Alonso
    • 1
  • M. Rocío Álvarez-López
    • 1
  • Jorge A. Martínez-Escribano
    • 2
  1. 1.Immunology DepartmentVirgen de la Arrixaca University HospitalMurciaSpain
  2. 2.Dermatology DepartmentVirgen de la Arrixaca University HospitalMurciaSpain

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