Advertisement

Lectin-like transcript 1 (LLT1) expression is associated with nodal metastasis in patients with head and neck cutaneous squamous cell carcinoma

  • J. Santos-JuanesEmail author
  • I. Fernández-Vega
  • S. Lorenzo-Herrero
  • C. Sordo-Bahamonde
  • P. Martínez-Camblor
  • J. M. García-Pedrero
  • B. Vivanco
  • C. Galache-Osuna
  • F. Vazquez-Lopez
  • S. Gonzalez
  • J. P. Rodrigo
Original Paper

Abstract

The interaction of lectin-like transcript 1 (LLT1) with CD161 inhibits Natural Killer cell activation. Overexpression of LLT1 contributes to the immunosuppressive properties of tumor cells. However, there are little data about LLT1 expression in human solid tumors. The objective of this paper is to investigate the relationship between LLT1 expression with the clinicopathologic features and its impact on the prognosis of head and neck cutaneous squamous cell carcinoma (cSCC). LLT1 expression was analyzed on paraffin-embedded tissue samples obtained from 100 patients with cSCC by immunohistochemistry. The estimator of Fine and Gray was used to estimate the cumulative incidence curves for relapse. Proportional Hazard models and Hazard ratios (HRs) were used for studying the risk of tumor relapse and mortality. LLT1 strong expression was a significant risk factor for nodal metastasis with crude and adjusted ratios (HRs) of 3.40 (95% CI 1.39–9.28) and 3.25 (95% CI 1.15–9.16); and for cSCC specific death of 6.17 (95% CI 1.79–21.2) and 6.10 (95% CI 1.45–25.7). Strong LLT1 expression is an independent predictor of nodal metastasis and poor disease-specific survival and it might be helpful for risk stratification of patients with cSCC.

Keywords

Cutaneous squamous cell carcinoma Lectin-like transcript 1 LLT1 Natural killer CLEC2D Immunohistochemistry Checkpoint 

Notes

Funding

This work was supported by the Spanish grant of Instituto de Salud Carlos III (PI16/01485) and FEDER European Union. SLH holds a Severo Ochoa Grant (BP14-150).

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

Ethical approval was obtained from the Hospital Universitario Central de Asturias Committee.

References

  1. 1.
    Aldemir H, Prod’homme V, Dumaurier MJ, Retiere C, Poupon G, Cazareth J, Bihl F, Braud VM (2005) Cutting edge: lectin-like transcript 1 is a ligand for the CD161 receptor. J Immunol 175(12):7791–7795CrossRefGoogle Scholar
  2. 2.
    Amin MB, Edge SB, Greene FL et al (eds) (2017) AJCC cancer staging manual, 8th edn. Springer, New YorkGoogle Scholar
  3. 3.
    Aust JG, Gays F, Mickiewicz KM, Buchanan E, Brooks CG (2009) The expression and function of the NKRP1 receptor family in C57BL/6 mice. J Immunol 183(1):106–116.  https://doi.org/10.4049/jimmunol.0804281 CrossRefGoogle Scholar
  4. 4.
    Azzoni L, Zatsepina O, Abebe B, Bennett IM, Kanakaraj P, Perussia B (1998) Differential transcriptional regulation of CD161 and a novel gene, 197/15a, by IL-2, IL-15, and IL-12 in NK and T cells. J Immunol. 161(7):3493–3500Google Scholar
  5. 5.
    Brantsch KD, Meisner C, Schönfisch B, Trilling B, Wehner-Caroli J, Röcken M, Breuniger H (2008) Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol 9(8):713–720.  https://doi.org/10.1016/S1470-2045(08)70178-5 CrossRefGoogle Scholar
  6. 6.
    Boles KS, Barten R, Kumaresan PR, Trowsdale J, Mathew PA (1999) Cloning of a new lectin-like receptor expressed on human NK cells. Immunogenetics 50(1–2):1–7CrossRefGoogle Scholar
  7. 7.
    Chalan P, Bijzet J, Huitema MG, Kroesen BJ, Brouwer E, Boots AM (2015) Expression of lectin-like transcript 1, the ligand for CD161, in rheumatoid arthritis. PLoS One 10(7):e0132436.  https://doi.org/10.1371/journal.pone.0132436 CrossRefGoogle Scholar
  8. 8.
    Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds) (2010) American Joint Committee on Cancer cancer staging manual, 7th edn. Springer, New YorkGoogle Scholar
  9. 9.
    Eigentler TK, Leiter U, Häfner H-M, Garbe C, Röcken M, Breuninger H (2017) Survival of patients with cutaneous squamous cell carcinoma: results of a prospective cohort study. J Invest Dermatol 137(11):2309–2315.  https://doi.org/10.1016/j.jid.2017.06.025 CrossRefGoogle Scholar
  10. 10.
    Eisemann N, Waldmann A, Geller AC, Weinstock MA, Volkmer B, Greinert R, Breitbart EW, Katalinic A (2014) Non-melanoma skin cancer incidence and impact of skin cancer screening on incidence. J Invest Dermatol 134(1):43–50.  https://doi.org/10.1038/jid.2013.304 CrossRefGoogle Scholar
  11. 11.
    Fine J, Gray R (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94(446):496–509CrossRefGoogle Scholar
  12. 12.
    Gray RJ (1998) A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16(3):1141–1154CrossRefGoogle Scholar
  13. 13.
    Gonzalez-Guerrero M, Martínez-Camblor P, Vivanco B, Fernández-Vega I, Munguía-Calzada P, Gonzalez-Gutierrez MP, Rodrigo JP, Galache C, Santos-Juanes J (2017) The adverse prognostic effect of tumor budding on the evolution of cutaneous head and neck squamous cell carcinoma. J Am Acad Dermatol 76(6):1139–1145.  https://doi.org/10.1016/j.jaad.2017.08.048 CrossRefGoogle Scholar
  14. 14.
    Karia PS, Han J, Schmults CD (2013) Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol 68(6):957–966.  https://doi.org/10.1016/j.jaad.2012.11.037 CrossRefGoogle Scholar
  15. 15.
    Karia PS, Jambusaria-Pahlajani A, Harrington DP, Murphy GF, Qureshi AA, Schmults CD (2014) Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol 32(4):327–334.  https://doi.org/10.1200/JCO.2012.48.5326 CrossRefGoogle Scholar
  16. 16.
    Llibre A, Garner L, Partridge A, Freeman GJ, Klenerman P, Willberg CB (2016) Expression of lectin-like transcript-1 in human tissues. F1000Res 5:2929.  https://doi.org/10.12688/f1000research.10009.1 (eCollection 2016) CrossRefGoogle Scholar
  17. 17.
    Llibre A, López-Macías C, Marafioti T, Mehta H, Partridge A, Kanzig C, Rivellese F, Galson JD, Walker LJ, Milne P, Phillips RE, Kelly DF, Freeman GJ, El Shikh ME, Klenerman P, Willberg CB (2016) LLT1 and CD161 expression in human germinal centers promotes B cell activation and CXCR4 downregulation. J Immunol 196(5):2085–2094.  https://doi.org/10.4049/jimmunol.1502462 CrossRefGoogle Scholar
  18. 18.
    Llibre A, Klenerman P, Willberg CB (2016) Multi-functional lectin-like transcript-1: a new player in human immune regulation. Immunol Lett 177:62–69.  https://doi.org/10.1016/j.imlet.2016.07.007 CrossRefGoogle Scholar
  19. 19.
    Mathew SO, Chaudhary P, Powers SB, Vishwanatha JK, Mathew PA (2016) Overexpression of LLT1 (OCIL, CLEC2D) on prostate cancer cells inhibits NK cell-mediated killing through LLT1-NKRP1A (CD161) interaction. Oncotarget 7(42):68650–68661.  https://doi.org/10.18632/oncotarget.11896 CrossRefGoogle Scholar
  20. 20.
    Marrufo AM, Matthew SO, Chaudhary P, Malaer JD, VIshwanatha JK, Mathew PA (2018) Blocking LLT1 (CLEC2D, OCIL)-NKRP1A (AD161) interaction enhances natural killer cell-mediated lysis of triple-negative breast cancer cells. Am J Cancer Res 1:1050–1063Google Scholar
  21. 21.
    Menéndez ST, Rodrigo JP, Alvarez-Teijeiro S, Villaronga MÁ, Allonca E, Vallina A, Astudillo A, Barros F, Suárez C, García-Pedrero JM (2012) Role of HERG1 potassium channel in both malignant transformation and disease progression in head and neck carcinomas. Mod Pathol 25(8):1069–1078.  https://doi.org/10.1038/modpathol.2012.63 CrossRefGoogle Scholar
  22. 22.
    Rangwala S, Tsai KY (2011) Roles of the immune system in skin cancer. Br J Dermatol 165(5):953–965.  https://doi.org/10.1111/j.1365-2133.2011.10507 CrossRefGoogle Scholar
  23. 23.
    Rosen DB, Bettadapura J, Alsharifi M, Mathew PA, Warren HS, Lanier LL (2005) Cutting edge: lectin-like transcript-1 is a ligand for the inhibitory human NKR-P1A receptor. J Immunol 175(12):7796–7799CrossRefGoogle Scholar
  24. 24.
    Roth P, Mittelbronn M, Wick W, Meyermann R, Tatagiba M, Weller M (2007) Malignant glioma cells counteract antitumor immune responses through expression of lectin-like transcript-1. Cancer Res 67(8):3540–3544.  https://doi.org/10.1158/0008-5472.CAN-06-4783 CrossRefGoogle Scholar
  25. 25.
    Satkunanathan S, Kumar N, Bajorek M, Purbhoo MA, Culley FJ (2014) Respiratory syncytial virus infection, TLR3 ligands, and proinflammatory cytokines induce CD161 ligand LLT1 expression on the respiratory epithelium. J Virol 88(5):2366–2373.  https://doi.org/10.1128/JVI.02789-13 CrossRefGoogle Scholar
  26. 26.
    von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP (2007) The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 370(9596):1453–1457CrossRefGoogle Scholar
  27. 27.
    Yu SH, Bordeaux JS, Baron ED (2014) The immune system and skin cancer. Adv Exp Med Biol 810:182–191Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • J. Santos-Juanes
    • 1
    • 2
    • 3
    Email author
  • I. Fernández-Vega
    • 4
    • 5
  • S. Lorenzo-Herrero
    • 3
    • 6
    • 7
  • C. Sordo-Bahamonde
    • 3
    • 6
    • 7
  • P. Martínez-Camblor
    • 8
  • J. M. García-Pedrero
    • 3
    • 6
  • B. Vivanco
    • 4
    • 5
  • C. Galache-Osuna
    • 1
  • F. Vazquez-Lopez
    • 1
    • 2
  • S. Gonzalez
    • 3
    • 6
    • 7
  • J. P. Rodrigo
    • 3
    • 6
    • 9
    • 10
  1. 1.Service of DermatologyHospital Universitario Central de AsturiasOviedoSpain
  2. 2.Departamento de MedicinaUniversidad de OviedoOviedoSpain
  3. 3.Instituto de Investigación Sanitaria del Principado de AsturiasOviedoSpain
  4. 4.Service of PathologyHospital Universitario Central de AsturiasOviedoSpain
  5. 5.Departamento de Cirugía y especialidades Médico-quirúrgicasUniversidad de OviedoOviedoSpain
  6. 6.Instituto Universitario de Oncología del Principado de AsturiasOviedoSpain
  7. 7.Department of Functional BiologyUniversity of OviedoOviedoSpain
  8. 8.Geisel School of Medicine at DartmouthDartmouth CollegeHannoverUSA
  9. 9.Department of OtolaryngologyHospital Universitario Central de Asturias and OviedoOviedoSpain
  10. 10.CIBERONCMadridSpain

Personalised recommendations