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Cancer/testis antigens can be immunological targets in clonogenic CD133+ melanoma cells

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Abstract

“Cancer stem cells” that resist conventional treatments may be a cause of therapeutic failure in melanoma. We report a subpopulation of clonogenic melanoma cells that are characterized by high prominin-1/CD133 expression in melanoma and melanoma cell lines. These cells have enhanced clonogenicity and self-renewal in vitro, and serve as a limited in vitro model for melanoma stem cells. In some cases clonogenic CD133+ melanoma cells show increased expression of some cancer/testis (CT) antigens. The expression of NY-ESO-1 in an HLA-A2 expressing cell line allowed CD133+ clonogenic melanoma cells to be targeted for killing in vitro by NY-ESO-1-specific CD8+ T-lymphocytes. Our in vitro findings raise the hypothesis that if melanoma stem cells express CT antigens in vivo that immune targeting of these antigens may be a viable clinical strategy for the adjuvant treatment of melanoma.

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Abbreviations

CT:

Cancer/testis

CTL:

Cytotoxic T-lymphocyte

CSC:

Cancer stem cell

References

  1. Thompson JF, Scolyer RA, Kefford RF (2005) Cutaneous melanoma. Lancet 365:687–701

    PubMed  CAS  Google Scholar 

  2. Phan GQ, Yang JC, Sherry RM et al (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377

    Article  PubMed  CAS  Google Scholar 

  3. Morgan RA, Dudley ME, Wunderlich JR et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129

    Article  PubMed  CAS  Google Scholar 

  4. Cebon J, Gedye C, John T et al (2007) Immunotherapy of advanced or metastatic melanoma. Clin Adv Hematol Oncol 5:994–1006

    PubMed  Google Scholar 

  5. Reya T, Morrison SJ, Clarke MF et al (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  PubMed  CAS  Google Scholar 

  6. Dalerba P, Cho RW, Clarke MF (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284

    Article  PubMed  CAS  Google Scholar 

  7. Polyak K, Hahn WC (2006) Roots and stems: stem cells in cancer. Nat Med 12:296–300

    Article  PubMed  CAS  Google Scholar 

  8. Brabletz T, Jung A, Spaderna S et al (2005) Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer 5:744–749

    Article  PubMed  CAS  Google Scholar 

  9. Kim JJ, Tannock IF (2005) Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer 5:516–525

    Article  PubMed  CAS  Google Scholar 

  10. Frank NY, Margaryan A, Huang Y et al (2005) ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 65:4320–4333

    Article  PubMed  CAS  Google Scholar 

  11. Fang D, Nguyen TK, Leishear K et al (2005) A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 65:9328–9337

    Article  PubMed  CAS  Google Scholar 

  12. Klein WM, Wu BP, Zhao S et al (2007) Increased expression of stem cell markers in malignant melanoma. Mod Pathol 20:102–107

    Article  PubMed  CAS  Google Scholar 

  13. Monzani E, Facchetti F, Galmozzi E et al (2007) Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer 43:935–946

    Article  PubMed  CAS  Google Scholar 

  14. Schatton T, Murphy GF, Frank NY et al (2008) Identification of cells initiating human melanomas. Nature 451:345–349

    Article  PubMed  CAS  Google Scholar 

  15. Quintana E, Shackleton M, Sabel MS et al (2008) Efficient tumour formation by single human melanoma cells. Nature 456:593–598

    Article  PubMed  CAS  Google Scholar 

  16. Scanlan MJ, Simpson AJ, Old LJ (2004) The cancer/testis genes: review, standardization, and commentary. Cancer Immun 4:1. http://www.cancerimmunity.org/v4p1/031220.htm

    PubMed  Google Scholar 

  17. Nicholaou T, Ebert L, Davis ID et al (2006) Directions in the immune targeting of cancer: lessons learned from the cancer-testis Ag NY-ESO-1. Immunol Cell Biol 84:303–317

    Article  PubMed  CAS  Google Scholar 

  18. Simpson AJ, Caballero OL, Jungbluth A et al (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5:615–625

    Article  PubMed  CAS  Google Scholar 

  19. Jäger D, Taverna C, Zippelius A et al (2004) Identification of tumor antigens as potential target antigens for immunotherapy by serological expression cloning. Cancer Immunol Immunother 53:144–147

    Article  PubMed  Google Scholar 

  20. Yang B, O’Herrin SM, Wu J et al (2007) MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Res 67:9954–9962

    Article  PubMed  CAS  Google Scholar 

  21. Laduron S, Deplus R, Zhou S et al (2004) MAGE-A1 interacts with adaptor SKIP and the deacetylase HDAC1 to repress transcription. Nucleic Acids Res 32:4340–4350

    Article  PubMed  CAS  Google Scholar 

  22. Cho HJ, Caballero OL, Gnjatic S et al (2006) Physical interaction of two cancer-testis antigens, MAGE-C1 (CT7) and NY-ESO-1 (CT6). Cancer Immun 6:12. http://www.cancerimmunity.org/v6p12/061012.htm

    PubMed  Google Scholar 

  23. Davis ID, Chen W, Jackson H et al (2004) Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4(+) and CD8(+) T cell responses in humans. Proc Natl Acad Sci USA 101:10697–10702

    Article  PubMed  CAS  Google Scholar 

  24. Fargeas CA, Fonseca A-V, Huttner WB et al (2006) Prominin–1 (CD133): from progenitor cells to human diseases. Future Lipidol 1:213–225

    Article  CAS  Google Scholar 

  25. Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

    Article  PubMed  CAS  Google Scholar 

  26. Belicchi M, Pisati F, Lopa R et al (2004) Human skin-derived stem cells migrate throughout forebrain and differentiate into astrocytes after injection into adult mouse brain. J Neurosci Res 77:475–486

    Article  PubMed  CAS  Google Scholar 

  27. Gibbs P, Hutchins AM, Dorian KT et al (2000) MAGE-12 and MAGE-6 are frequently expressed in malignant melanoma. Melanoma Res 10:259–264

    Article  PubMed  CAS  Google Scholar 

  28. Carey TE, Takahashi T, Resnick LA et al (1976) Cell surface antigens of human malignant melanoma: mixed hemadsorption assays for humoral immunity to cultured autologous melanoma cells. Proc Natl Acad Sci USA 73:3278–3282

    Article  PubMed  CAS  Google Scholar 

  29. Karbanova J, Missol-Kolka E, Fonseca AV et al (2008) The stem cell marker CD133 (Prominin-1) is expressed in various human glandular epithelia. J Histochem Cytochem 56:977–993

    Article  PubMed  CAS  Google Scholar 

  30. Barrow C, Browning J, MacGregor D et al (2006) Tumor antigen expression in melanoma varies according to antigen and stage. Clin Cancer Res 12:764–771

    Article  PubMed  CAS  Google Scholar 

  31. Jungbluth AA, Chen YT, Busam KJ et al (2002) CT7 (MAGE-C1) antigen expression in normal and neoplastic tissues. Int J Cancer 99:839–845

    Article  PubMed  CAS  Google Scholar 

  32. Vaughan HA, Svobodova S, MacGregor D et al (2004) Immunohistochemical and molecular analysis of human melanomas for expression of the human cancer-testis antigens NY-ESO-1 and LAGE-1. Clin Cancer Res 10:8396–8404

    Article  PubMed  CAS  Google Scholar 

  33. Chen JL, Dunbar PR, Gileadi U et al (2000) Identification of NY-ESO-1 peptide analogues capable of improved stimulation of tumor-reactive CTL. J Immunol 165:948–955

    PubMed  CAS  Google Scholar 

  34. Lev DC, Onn A, Melinkova VO et al (2004) Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol 22:2092–2100

    Article  PubMed  CAS  Google Scholar 

  35. Grichnik JM, Burch JA, Schulteis RD et al (2006) Melanoma, a tumor based on a mutant stem cell? J Invest Dermatol 126:142–153

    Article  PubMed  CAS  Google Scholar 

  36. Clarke MF (2005) A self-renewal assay for cancer stem cells. Cancer Chemother Pharmacol 56(Suppl 7):64–68

    Article  PubMed  Google Scholar 

  37. Jaksch M, Munera J, Bajpai R et al (2008) Cell cycle-dependent variation of a CD133 epitope in human embryonic stem cell, colon cancer, and melanoma cell lines. Cancer Res 68:7882–7886

    Article  PubMed  CAS  Google Scholar 

  38. Herlyn M, Balaban G, Bennicelli J et al (1985) Primary melanoma cells of the vertical growth phase: similarities to metastatic cells. J Natl Cancer Inst 74:283–289

    PubMed  CAS  Google Scholar 

  39. Lee J, Kotliarova S, Kotliarov Y et al (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9:391–403

    Article  PubMed  CAS  Google Scholar 

  40. Li A, Walling J, Kotliarov Y et al (2008) Genomic changes and gene expression profiles reveal that established glioma cell lines are poorly representative of primary human gliomas. Mol Cancer Res 6:21–30

    Article  PubMed  CAS  Google Scholar 

  41. De Witt Hamer PC, Van Tilborg AA, Eijk PP et al (2008) The genomic profile of human malignant glioma is altered early in primary cell culture and preserved in spheroids. Oncogene 27:2091–2096

    Article  PubMed  Google Scholar 

  42. Vogl A, Sartorius U, Vogt T et al (2005) Gene expression profile changes between melanoma metastases and their daughter cell lines: implication for vaccination protocols. J Investig Dermatol 124:401–404

    Article  PubMed  CAS  Google Scholar 

  43. Sigalotti L, Covre A, Zabierowski S et al (2008) Cancer testis antigens in human melanoma stem cells: expression, distribution, and methylation status. J Cell Physiol 215:287–291

    Article  PubMed  CAS  Google Scholar 

  44. Gjerstorff MF, Johansen LE, Nielsen O et al (2006) Restriction of GAGE protein expression to subpopulations of cancer cells is independent of genotype and may limit the use of GAGE proteins as targets for cancer immunotherapy. Br J Cancer 94:1864–1873

    Article  PubMed  CAS  Google Scholar 

  45. Adair SJ, Hogan KT (2008) Treatment of ovarian cancer cell lines with 5-aza–2′-deoxycytidine upregulates the expression of cancer-testis antigens and class I major histocompatibility complex-encoded molecules. Cancer Immunol Immunother. doi:10.1007/s00262-008-0582-6

  46. Rappa G, Fodstad O, Lorico A (2008) The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma. Stem Cells 26:3008–3017

    Article  PubMed  CAS  Google Scholar 

  47. Yu JS (2008) Inventor. CEDARS-SINAI MEDICAL CENTER; 8700 Beverly Boulevard, Los Angeles, CA 90048 assignee. Cancer stem cell antigen vaccines and methods. US patent WO/2008/039874, 3 April 2008. http://www.wipo.int/pctdb/en/wo.jsp?WO=2008039874&IA=US2007079600&DISPLAY=STATUS

  48. Smith LM, Nesterova A, Ryan MC et al (2008) CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer 99:100–109

    Article  PubMed  CAS  Google Scholar 

  49. Florek M, Haase M, Marzesco AM et al (2005) Prominin-1/CD133, a neural and hematopoietic stem cell marker, is expressed in adult human differentiated cells and certain types of kidney cancer. Cell Tissue Res 319:15–26

    Article  PubMed  CAS  Google Scholar 

  50. Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45

    Article  PubMed  CAS  Google Scholar 

  51. Frank M (2007) Inventor. The Brigham and Women’s Hospital, Inc., Boston, MA., assignee. ABCB5 positive mesenchymal stem cells as immunomodulators. US Patent WO/2007/143139, 31 May 2007. http://www.wipo.int/pctdb/en/wo.jsp?WO=2007143139

  52. Ménard C, Martin F, Apetoh L et al (2008) Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother 57:1579–1587

    Article  PubMed  Google Scholar 

  53. Mine T, Matsueda S, Li Y et al (2008) Breast cancer cells expressing stem cell markers CD44(+) CD24 (lo) are eliminated by Numb-1 peptide-activated T cells. Cancer Immunol Immunother. doi:10.1007/s00262-008-0623-1

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Acknowledgments

CG was supported by a National Health and Medical Research Council of Australia (NHMRC) Postgraduate Medical Scholarship. IDD is supported by a Victorian Cancer Agency Clinical Researcher Fellowship and is an Honorary National Health and Medical Research Council (NHMRC) Practitioner Fellow. JC is supported by an NHMRC Practitioner Fellowship. This project received the support of the Harry J Lloyd Charitable Trust. Thanks to the melanoma patients attending the Ludwig/Austin Melanoma Clinic, Ken Field (ImmunoID) and Paula Stoddart (Miltenyi Biotec) for technical assistance, and Dr Mark Shackleton (Walter and Eliza Hall Institute) and Dr. Otavia Caballero, Dr. Andy Simpson and Dr. Lloyd Old (LICR New York) for helpful comments and advice.

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Correspondence to Jonathan Cebon.

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Gedye, C., Quirk, J., Browning, J. et al. Cancer/testis antigens can be immunological targets in clonogenic CD133+ melanoma cells. Cancer Immunol Immunother 58, 1635–1646 (2009). https://doi.org/10.1007/s00262-009-0672-0

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  • DOI: https://doi.org/10.1007/s00262-009-0672-0

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