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Role of CD44 in lymphokine-activated killer cell-mediated killing of melanoma

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Abstract

In the current study, we examined the potential significance of CD44 expression on lymphokine-activated killer (LAK) cells in their interaction and killing of melanoma cells. Stimulation of splenocytes with IL-2 led to a significant increase in the expression of CD44 on T cells, NK cells, and NKT cells. Treatment of melanoma-bearing CD44 WT mice with IL-2 led to a significant reduction in the local tumor growth while treatment of melanoma-bearing CD44 KO mice with IL-2 was ineffective at controlling tumor growth. Furthermore, the ability of splenocytes from IL-2-treated CD44 KO mice to kill melanoma tumor targets was significantly reduced when compared to the anti-tumor activity of splenocytes from IL-2-treated CD44 WT mice. The importance of CD44 expression on the LAK cells was further confirmed by the observation that adoptively transferred CD44 WT LAK cells were significantly more effective than CD44 KO LAK cells at controlling tumor growth in vivo. Next, the significance of the increased expression of CD44 in tumor killing was examined and showed that following stimulation with IL-2, distinct populations of cells with low (CD44lo) or elevated (CD44hi) expression of CD44 are generated and that the CD44hi cells are responsible for killing of the melanoma cells. The reduced killing activity of the CD44 KO LAK cells did not result from reduced activation or expression of effector molecules but was due, at least in part, to a reduced ability to adhere to B16F10 tumor cells.

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References

  1. Tucker MA, Goldstein AM (2003) Melanoma etiology: where are we? Oncogene 22(20):3042–3052

    Article  PubMed  CAS  Google Scholar 

  2. Valmori D, Scheibenbogen C, Dutoit V, Nagorsen D, Asemissen AM, Rubio-Godoy V, Rimoldi D, Guillaume P, Romero P, Schadendorf D, Lipp M, Dietrich PY, Thiel E, Cerottini JC, Lienard D, Keilholz U (2002) Circulating tumor-reactive CD8(+) T cells in melanoma patients contain a CD45RA(+)CCR7(−) effector subset exerting ex vivo tumor-specific cytolytic activity. Cancer Res 62(6):1743–1750

    PubMed  CAS  Google Scholar 

  3. Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA (2003) Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother 26(4):332–342

    Article  PubMed  Google Scholar 

  4. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE (1994) Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271(12):907–913

    Article  PubMed  CAS  Google Scholar 

  5. Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL (1985) Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 161(5):1169–1188

    Article  PubMed  CAS  Google Scholar 

  6. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC (1995) Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13(3):688–696

    PubMed  CAS  Google Scholar 

  7. van Weering DH, Baas PD, Bos JL (1993) A PCR-based method for the analysis of human CD44 splice products. PCR Methods Appl 3(2):100–106

    PubMed  Google Scholar 

  8. Goodison S, Urquidi V, Tarin D (1999) CD44 cell adhesion molecules. Mol Pathol 52(4):189–196

    Article  PubMed  CAS  Google Scholar 

  9. Galandrini R, Albi N, Tripodi G, Zarcone D, Terenzi A, Moretta A, Grossi CE, Velardi A (1993) Antibodies to CD44 trigger effector functions of human T cell clones. J Immunol 150(10):4225–4235

    PubMed  CAS  Google Scholar 

  10. Tan PH, Santos EB, Rossbach HC, Sandmaier BM (1993) Enhancement of natural killer activity by an antibody to CD44. J Immunol 150(3):812–820

    PubMed  CAS  Google Scholar 

  11. Seth A, Gote L, Nagarkatti M, Nagarkatti PS (1991) T-cell-receptor-independent activation of cytolytic activity of cytotoxic T lymphocytes mediated through CD44 and gp90MEL-14. Proc Natl Acad Sci USA 88(17):7877–7881

    Article  PubMed  CAS  Google Scholar 

  12. Hammond DM, Nagarkatti PS, Gote LR, Seth A, Hassuneh MR, Nagarkatti M (1993) Double-negative T cells from MRL-lpr/lpr mice mediate cytolytic activity when triggered through adhesion molecules and constitutively express perforin gene. J Exp Med 178(6):2225–2230

    Article  PubMed  CAS  Google Scholar 

  13. Schmits R, Filmus J, Gerwin N, Senaldi G, Kiefer F, Kundig T, Wakeham A, Shahinian A, Catzavelos C, Rak J, Furlonger C, Zakarian A, Simard JJ, Ohashi PS, Paige CJ, Gutierrez-Ramos JC, Mak TW (1997) CD44 regulates hematopoietic progenitor distribution, granuloma formation, and tumorigenicity. Blood 90(6):2217–2233

    PubMed  CAS  Google Scholar 

  14. Rafi-Janajreh AQ, Chen D, Schmits R, Mak TW, Grayson RL, Sponenberg DP, Nagarkatti M, Nagarkatti PS (1999) Evidence for the involvement of CD44 in endothelial cell injury and induction of vascular leak syndrome by IL-2. J Immunol 163(3):1619–1627

    PubMed  CAS  Google Scholar 

  15. McKallip RJ, Fisher M, Do Y, Szakal AK, Gunthert U, Nagarkatti PS, Nagarkatti M (2003) Targeted deletion of CD44v7 exon leads to decreased endothelial cell injury but not tumor cell killing mediated by IL-2 activated cytolytic lymphocytes. J Biol Chem 278(44):43818–43830

    Google Scholar 

  16. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3(6):1101–1108

    Article  PubMed  CAS  Google Scholar 

  17. Wittig B, Schwarzler C, Fohr N, Gunthert U, Zoller M (1998) Curative treatment of an experimentally induced colitis by a CD44 variant V7-specific antibody. J Immunol 161(3):1069–1073

    PubMed  CAS  Google Scholar 

  18. McKallip RJ, Fisher M, Do Y, Szakal AK, Gunthert U, Nagarkatti PS, Nagarkatti M (2003) Targeted deletion of CD44v7 exon leads to decreased endothelial cell injury but not tumor cell killing mediated by interleukin-2-activated cytolytic lymphocytes. J Biol Chem 278(44):43818–43830. doi:10.1074/jbc.M304467200

    Article  PubMed  CAS  Google Scholar 

  19. Stinchcombe JC, Bossi G, Booth S, Griffiths GM (2001) The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15(5):751–761

    Article  PubMed  CAS  Google Scholar 

  20. Kadison AS, Morton DL (2003) Immunotherapy of malignant melanoma. Surg Clin North Am 83(2):343–370

    Article  PubMed  Google Scholar 

  21. Hershkovitz L, Schachter J, Treves AJ, Besser MJ (2010) Focus on adoptive T cell transfer trials in melanoma. Clin Dev Immunol 2010:260267. doi:10.1155/2010/260267

  22. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. doi:10.1056/NEJMoa1003466

    Google Scholar 

  23. Arai S, Meagher R, Swearingen M, Myint H, Rich E, Martinson J, Klingemann H (2008) Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 10(6):625–632. doi:10.1080/14653240802301872

    Article  PubMed  CAS  Google Scholar 

  24. Tam YK, Miyagawa B, Ho VC, Klingemann HG (1999) Immunotherapy of malignant melanoma in a SCID mouse model using the highly cytotoxic natural killer cell line NK-92. J Hematother 8(3):281–290

    Article  PubMed  CAS  Google Scholar 

  25. Raulet DH (1994) MHC class I-deficient mice. Adv Immunol 55:381–421

    Article  PubMed  CAS  Google Scholar 

  26. Fujita S, Puri RK, Yu ZX, Travis WD, Ferrans VJ (1991) An ultrastructural study of in vivo interactions between lymphocytes and endothelial cells in the pathogenesis of the vascular leak syndrome induced by interleukin-2. Cancer 68(10):2169–2174

    Article  PubMed  CAS  Google Scholar 

  27. Rafi-Janajreh AQ, Nagarkatti PS, Nagarkatti M (1998) Role of CD44 in CTL and NK cell activity. Front Biosci 3:D665–D671

    PubMed  CAS  Google Scholar 

  28. Anikeeva N, Somersalo K, Sims TN, Thomas VK, Dustin ML, Sykulev Y (2005) Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes. Proc Natl Acad Sci USA 102(18):6437–6442. doi:10.1073/pnas.0502467102

    Article  PubMed  CAS  Google Scholar 

  29. Somersalo K, Anikeeva N, Sims TN, Thomas VK, Strong RK, Spies T, Lebedeva T, Sykulev Y, Dustin ML (2004) Cytotoxic T lymphocytes form an antigen-independent ring junction. J Clin Invest 113(1):49–57. doi:10.1172/JCI19337

    PubMed  CAS  Google Scholar 

  30. Krensky AM, Robbins E, Springer TA, Burakoff SJ (1984) LFA-1, LFA-2, and LFA-3 antigens are involved in CTL-target conjugation. J Immunol 132(5):2180–2182

    PubMed  CAS  Google Scholar 

  31. Dustin ML, Springer TA (1989) T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature 341(6243):619–624. doi:10.1038/341619a0

    Article  PubMed  CAS  Google Scholar 

  32. Davis DM, Chiu I, Fassett M, Cohen GB, Mandelboim O, Strominger JL (1999) The human natural killer cell immune synapse. Proc Natl Acad Sci USA 96(26):15062–15067

    Article  PubMed  CAS  Google Scholar 

  33. Orange JS, Harris KE, Andzelm MM, Valter MM, Geha RS, Strominger JL (2003) The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proc Natl Acad Sci USA 100(24):14151–14156. doi:10.1073/pnas.1835830100

    Article  PubMed  CAS  Google Scholar 

  34. Zheng X, Wang Y, Wei H, Sun R, Tian Z (2009) LFA-1 and CD2 synergize for the Erk1/2 activation in the natural killer (NK) cell immunological synapse. J Biol Chem 284(32):21280–21287. doi:10.1074/jbc.M807053200

    Article  PubMed  CAS  Google Scholar 

  35. Hegde VL, Singh NP, Nagarkatti PS, Nagarkatti M (2008) CD44 mobilization in allogeneic dendritic cell-T cell immunological synapse plays a key role in T cell activation. J Leukoc Biol 84(1):134–142. doi:10.1189/jlb.1107752

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by a Cancer Research Award from the Georgia Cancer Coalition and a grant from the National Institutes of Health (K22-CA109334).

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The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Division of Basic Medical Sciences, Mercer University School of Medicine, 1550 College St, Macon, GA, 31207, USA

    Jingping Sun, Gabriela P. Law & Robert J. McKallip

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  1. Jingping Sun
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  2. Gabriela P. Law
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  3. Robert J. McKallip
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Correspondence to Robert J. McKallip.

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Sun, J., Law, G.P. & McKallip, R.J. Role of CD44 in lymphokine-activated killer cell-mediated killing of melanoma. Cancer Immunol Immunother 61, 323–334 (2012). https://doi.org/10.1007/s00262-011-1105-4

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  • DOI: https://doi.org/10.1007/s00262-011-1105-4

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