Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Sep 27;91(20):9461–9465. doi: 10.1073/pnas.91.20.9461

Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tyrosinase gene.

S L Topalian 1, L Rivoltini 1, M Mancini 1, N R Markus 1, P F Robbins 1, Y Kawakami 1, S A Rosenberg 1
PMCID: PMC44832  PMID: 7937789

Abstract

Although commonly expressed human melanoma-associated antigens recognized by CD8+ cytolytic T cells have been described, little is known about CD4+ T-cell recognition of melanoma-associated antigens. Epstein-Barr virus-transformed B cells were used to present antigens derived from whole cell lysates of autologous and allogeneic melanomas for recognition by melanoma-specific CD4+ T-cell lines and clones cultured from tumor-infiltrating lymphocytes. HLA-DR-restricted antigens were detected in the lysates on the basis of specific release of cytokines from the responding T cells. Antigen sharing was demonstrated in the majority of melanomas tested, as well as in cultured normal melanocytes, but not in other normal tissues or nonmelanoma tumors. T-cell clones manifested a single recognition pattern, suggesting the presence of an immunodominant epitope. This epitope was identified as a product of the tyrosinase gene, which has also been shown to encode class I-restricted epitopes recognized by CD8+ T cells from melanoma patients. Identification of commonly expressed tumor-associated protein molecules containing epitopes presented by both class I and class II major histocompatibility molecules may provide optimal reagents for cancer immunization strategies.

Full text

PDF
9461

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anichini A., Maccalli C., Mortarini R., Salvi S., Mazzocchi A., Squarcina P., Herlyn M., Parmiani G. Melanoma cells and normal melanocytes share antigens recognized by HLA-A2-restricted cytotoxic T cell clones from melanoma patients. J Exp Med. 1993 Apr 1;177(4):989–998. doi: 10.1084/jem.177.4.989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bakker A. B., Schreurs M. W., de Boer A. J., Kawakami Y., Rosenberg S. A., Adema G. J., Figdor C. G. Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes. J Exp Med. 1994 Mar 1;179(3):1005–1009. doi: 10.1084/jem.179.3.1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Belldegrun A., Kasid A., Uppenkamp M., Topalian S. L., Rosenberg S. A. Human tumor infiltrating lymphocytes. Analysis of lymphokine mRNA expression and relevance to cancer immunotherapy. J Immunol. 1989 Jun 15;142(12):4520–4526. [PubMed] [Google Scholar]
  4. Bouchard B., Fuller B. B., Vijayasaradhi S., Houghton A. N. Induction of pigmentation in mouse fibroblasts by expression of human tyrosinase cDNA. J Exp Med. 1989 Jun 1;169(6):2029–2042. doi: 10.1084/jem.169.6.2029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brichard V., Van Pel A., Wölfel T., Wölfel C., De Plaen E., Lethé B., Coulie P., Boon T. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med. 1993 Aug 1;178(2):489–495. doi: 10.1084/jem.178.2.489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen Q., Hersey P. MHC-restricted responses of CD8+ and CD4+ T-cell clones from regional lymph nodes of melanoma patients. Int J Cancer. 1992 May 8;51(2):218–224. doi: 10.1002/ijc.2910510209. [DOI] [PubMed] [Google Scholar]
  7. Darrow T. L., Slingluff C. L., Jr, Seigler H. F. The role of HLA class I antigens in recognition of melanoma cells by tumor-specific cytotoxic T lymphocytes. Evidence for shared tumor antigens. J Immunol. 1989 May 1;142(9):3329–3335. [PubMed] [Google Scholar]
  8. Dranoff G., Jaffee E., Lazenby A., Golumbek P., Levitsky H., Brose K., Jackson V., Hamada H., Pardoll D., Mulligan R. C. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539–3543. doi: 10.1073/pnas.90.8.3539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gaugler B., Van den Eynde B., van der Bruggen P., Romero P., Gaforio J. J., De Plaen E., Lethé B., Brasseur F., Boon T. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med. 1994 Mar 1;179(3):921–930. doi: 10.1084/jem.179.3.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Greenberg P. D., Kern D. E., Cheever M. A. Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+,2- T cells. Tumor eradication does not require participation of cytotoxic T cells. J Exp Med. 1985 May 1;161(5):1122–1134. doi: 10.1084/jem.161.5.1122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gregersen P. K., Shen M., Song Q. L., Merryman P., Degar S., Seki T., Maccari J., Goldberg D., Murphy H., Schwenzer J. Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2642–2646. doi: 10.1073/pnas.83.8.2642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Herlyn M., Thurin J., Balaban G., Bennicelli J. L., Herlyn D., Elder D. E., Bondi E., Guerry D., Nowell P., Clark W. H. Characteristics of cultured human melanocytes isolated from different stages of tumor progression. Cancer Res. 1985 Nov;45(11 Pt 2):5670–5676. [PubMed] [Google Scholar]
  13. Hom S. S., Schwartzentruber D. J., Rosenberg S. A., Topalian S. L. Specific release of cytokines by lymphocytes infiltrating human melanomas in response to shared melanoma antigens. J Immunother Emphasis Tumor Immunol. 1993 Jan;13(1):18–30. doi: 10.1097/00002371-199301000-00003. [DOI] [PubMed] [Google Scholar]
  14. Hom S. S., Topalian S. L., Simonis T., Mancini M., Rosenberg S. A. Common expression of melanoma tumor-associated antigens recognized by human tumor infiltrating lymphocytes: analysis by human lymphocyte antigen restriction. J Immunother (1991) 1991 Jun;10(3):153–164. [PubMed] [Google Scholar]
  15. Kawakami Y., Eliyahu S., Delgado C. H., Robbins P. F., Rivoltini L., Topalian S. L., Miki T., Rosenberg S. A. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3515–3519. doi: 10.1073/pnas.91.9.3515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kawakami Y., Eliyahu S., Delgado C. H., Robbins P. F., Sakaguchi K., Appella E., Yannelli J. R., Adema G. J., Miki T., Rosenberg S. A. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6458–6462. doi: 10.1073/pnas.91.14.6458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kawakami Y., Zakut R., Topalian S. L., Stötter H., Rosenberg S. A. Shared human melanoma antigens. Recognition by tumor-infiltrating lymphocytes in HLA-A2.1-transfected melanomas. J Immunol. 1992 Jan 15;148(2):638–643. [PubMed] [Google Scholar]
  18. Kern D. E., Klarnet J. P., Jensen M. C., Greenberg P. D. Requirement for recognition of class II molecules and processed tumor antigen for optimal generation of syngeneic tumor-specific class I-restricted CTL. J Immunol. 1986 Jun 1;136(11):4303–4310. [PubMed] [Google Scholar]
  19. LeMay L. G., Kan-Mitchell J., Goedegebuure P., Harel W., Mitchell M. S. Detection of melanoma-reactive CD4+ HLA-class I-restricted cytotoxic T cell clones with long-term assay and pretreatment of targets with interferon-gamma. Cancer Immunol Immunother. 1993 Aug;37(3):187–194. doi: 10.1007/BF01525434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Miki T., Fleming T. P., Crescenzi M., Molloy C. J., Blam S. B., Reynolds S. H., Aaronson S. A. Development of a highly efficient expression cDNA cloning system: application to oncogene isolation. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5167–5171. doi: 10.1073/pnas.88.12.5167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Morecki S., Topalian S. L., Myers W. W., Okrongly D., Okarma T. B., Rosenberg S. A. Separation and growth of human CD4+ and CD8+ tumor-infiltrating lymphocytes and peripheral blood mononuclear cells by direct positive panning on covalently attached monoclonal antibody-coated flasks. J Biol Response Mod. 1990 Oct;9(5):463–474. [PubMed] [Google Scholar]
  22. Mukherji B., Guha A., Chakraborty N. G., Sivanandham M., Nashed A. L., Sporn J. R., Ergin M. T. Clonal analysis of cytotoxic and regulatory T cell responses against human melanoma. J Exp Med. 1989 Jun 1;169(6):1961–1976. doi: 10.1084/jem.169.6.1961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Naeyaert J. M., Eller M., Gordon P. R., Park H. Y., Gilchrest B. A. Pigment content of cultured human melanocytes does not correlate with tyrosinase message level. Br J Dermatol. 1991 Oct;125(4):297–303. doi: 10.1111/j.1365-2133.1991.tb14161.x. [DOI] [PubMed] [Google Scholar]
  24. O'Neil B. H., Kawakami Y., Restifo N. P., Bennink J. R., Yewdell J. W., Rosenberg S. A. Detection of shared MHC-restricted human melanoma antigens after vaccinia virus-mediated transduction of genes coding for HLA. J Immunol. 1993 Aug 1;151(3):1410–1418. [PMC free article] [PubMed] [Google Scholar]
  25. Ostrand-Rosenberg S., Roby C. A., Clements V. K. Abrogation of tumorigenicity by MHC class II antigen expression requires the cytoplasmic domain of the class II molecule. J Immunol. 1991 Oct 1;147(7):2419–2422. [PubMed] [Google Scholar]
  26. Petersdorf E. W., Smith A. G., Mickelson E. M., Martin P. J., Hansen J. A. Ten HLA-DR4 alleles defined by sequence polymorphisms within the DRB1 first domain. Immunogenetics. 1991;33(4):267–275. doi: 10.1007/BF00230505. [DOI] [PubMed] [Google Scholar]
  27. Radrizzani M., Benedetti B., Castelli C., Longo A., Ferrara G. B., Herlyn M., Parmiani G., Fossati G. Human allogeneic melanoma-reactive T-helper lymphocyte clones: functional analysis of lymphocyte-melanoma interactions. Int J Cancer. 1991 Dec 2;49(6):823–830. doi: 10.1002/ijc.2910490605. [DOI] [PubMed] [Google Scholar]
  28. Restifo N. P., Esquivel F., Kawakami Y., Yewdell J. W., Mulé J. J., Rosenberg S. A., Bennink J. R. Identification of human cancers deficient in antigen processing. J Exp Med. 1993 Feb 1;177(2):265–272. doi: 10.1084/jem.177.2.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Robbins P. F., el-Gamil M., Kawakami Y., Stevens E., Yannelli J. R., Rosenberg S. A. Recognition of tyrosinase by tumor-infiltrating lymphocytes from a patient responding to immunotherapy. Cancer Res. 1994 Jun 15;54(12):3124–3126. [PubMed] [Google Scholar]
  30. Seed B., Aruffo A. Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure. Proc Natl Acad Sci U S A. 1987 May;84(10):3365–3369. doi: 10.1073/pnas.84.10.3365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Slingluff C. L., Jr, Cox A. L., Henderson R. A., Hunt D. F., Engelhard V. H. Recognition of human melanoma cells by HLA-A2.1-restricted cytotoxic T lymphocytes is mediated by at least six shared peptide epitopes. J Immunol. 1993 Apr 1;150(7):2955–2963. [PubMed] [Google Scholar]
  32. Storkus W. J., Zeh H. J., 3rd, Maeurer M. J., Salter R. D., Lotze M. T. Identification of human melanoma peptides recognized by class I restricted tumor infiltrating T lymphocytes. J Immunol. 1993 Oct 1;151(7):3719–3727. [PubMed] [Google Scholar]
  33. Tiercy J. M., Gorski J., Jeannet M., Mach B. Identification and distribution of three serologically undetected alleles of HLA-DR by oligonucleotide.DNA typing analysis. Proc Natl Acad Sci U S A. 1988 Jan;85(1):198–202. doi: 10.1073/pnas.85.1.198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Topalian S. L., Kasid A., Rosenberg S. A. Immunoselection of a human melanoma resistant to specific lysis by autologous tumor-infiltrating lymphocytes. Possible mechanisms for immunotherapeutic failures. J Immunol. 1990 Jun 1;144(11):4487–4495. [PubMed] [Google Scholar]
  35. Topalian S. L., Muul L. M., Solomon D., Rosenberg S. A. Expansion of human tumor infiltrating lymphocytes for use in immunotherapy trials. J Immunol Methods. 1987 Aug 24;102(1):127–141. doi: 10.1016/s0022-1759(87)80018-2. [DOI] [PubMed] [Google Scholar]
  36. Topalian S. L., Rivoltini L., Mancini M., Ng J., Hartzman R. J., Rosenberg S. A. Melanoma-specific CD4+ T lymphocytes recognize human melanoma antigens processed and presented by Epstein-Barr virus-transformed B cells. Int J Cancer. 1994 Jul 1;58(1):69–79. doi: 10.1002/ijc.2910580113. [DOI] [PubMed] [Google Scholar]
  37. Topalian S. L., Solomon D., Rosenberg S. A. Tumor-specific cytolysis by lymphocytes infiltrating human melanomas. J Immunol. 1989 May 15;142(10):3714–3725. [PubMed] [Google Scholar]
  38. Van den Eynde B., Hainaut P., Hérin M., Knuth A., Lemoine C., Weynants P., van der Bruggen P., Fauchet R., Boon T. Presence on a human melanoma of multiple antigens recognized by autologous CTL. Int J Cancer. 1989 Oct 15;44(4):634–640. doi: 10.1002/ijc.2910440413. [DOI] [PubMed] [Google Scholar]
  39. Vijayasaradhi S., Bouchard B., Houghton A. N. The melanoma antigen gp75 is the human homologue of the mouse b (brown) locus gene product. J Exp Med. 1990 Apr 1;171(4):1375–1380. doi: 10.1084/jem.171.4.1375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wölfel T., Hauer M., Klehmann E., Brichard V., Ackermann B., Knuth A., Boon T., Meyer Zum Büschenfelde K. H. Analysis of antigens recognized on human melanoma cells by A2-restricted cytolytic T lymphocytes (CTL). Int J Cancer. 1993 Sep 9;55(2):237–244. doi: 10.1002/ijc.2910550212. [DOI] [PubMed] [Google Scholar]
  41. van der Bruggen P., Traversari C., Chomez P., Lurquin C., De Plaen E., Van den Eynde B., Knuth A., Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991 Dec 13;254(5038):1643–1647. doi: 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES