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. 1989 Sep 1;170(3):797–810. doi: 10.1084/jem.170.3.797

Lysis of human melanoma cells by autologous cytolytic T cell clones. Identification of human histocompatibility leukocyte antigen A2 as a restriction element for three different antigens

PMCID: PMC2189434  PMID: 2788708

Abstract

From the peripheral blood of the melanoma patient (AV), we derived cytolytic T lymphocyte (CTL) clones that lysed the autologous tumor line SK-MEL-29, but not autologous EBV-B cells, K562, and other tumor targets. By immunoselection experiments it was shown that the CTL clones recognized at least three different antigens on the autologous tumor cells. We demonstrate here that these melanoma antigens are presented to the CTL in association with HLA-A2. First, HLA-A2-reactive pregnancy sera as well as an mAb against HLA-A2 inhibited the CTL lysis. Second, immunoselected melanoma subclones that were resistant to lysis by CTL clones against the three antigens described were found to lack expression of HLA-A2. By sensitizing the patient's lymphocytes against an HLA-A2- melanoma clone, we established a new series of CTL clones recognizing autologous AV melanoma cells. However, efficient lysis was only seen when target cells were pretreated with IFN-gamma. The lytic activity of these CTL was selectively inhibited by an mAb against a common HLA-B determinant. These results indicate that in addition to HLA-A2, other class I antigens are involved in the recognition of AV melanoma cells by autologous CTL.

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Selected References

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  1. Barnstable C. J., Bodmer W. F., Brown G., Galfre G., Milstein C., Williams A. F., Ziegler A. Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens-new tools for genetic analysis. Cell. 1978 May;14(1):9–20. doi: 10.1016/0092-8674(78)90296-9. [DOI] [PubMed] [Google Scholar]
  2. Berke G., Amos D. B. Cytotoxic lymphocytes in the absence of detectable antibody. Nat New Biol. 1973 Apr 25;242(121):237–239. doi: 10.1038/newbio242237a0. [DOI] [PubMed] [Google Scholar]
  3. Bernards R., Dessain S. K., Weinberg R. A. N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma. Cell. 1986 Dec 5;47(5):667–674. doi: 10.1016/0092-8674(86)90509-x. [DOI] [PubMed] [Google Scholar]
  4. Bhan A. K., DesMarais C. L. Immunohistologic characterization of major histocompatibility antigens and inflammatory cellular infiltrate in human breast cancer. J Natl Cancer Inst. 1983 Sep;71(3):507–516. [PubMed] [Google Scholar]
  5. De Plaen E., Lurquin C., Van Pel A., Mariamé B., Szikora J. P., Wölfel T., Sibille C., Chomez P., Boon T. Immunogenic (tum-) variants of mouse tumor P815: cloning of the gene of tum- antigen P91A and identification of the tum- mutation. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2274–2278. doi: 10.1073/pnas.85.7.2274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Devos R., Plaetinck G., Cheroutre H., Simons G., Degrave W., Tavernier J., Remaut E., Fiers W. Molecular cloning of human interleukin 2 cDNA and its expression in E. coli. Nucleic Acids Res. 1983 Jul 11;11(13):4307–4323. doi: 10.1093/nar/11.13.4307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Doyle A., Martin W. J., Funa K., Gazdar A., Carney D., Martin S. E., Linnoila I., Cuttitta F., Mulshine J., Bunn P. Markedly decreased expression of class I histocompatibility antigens, protein, and mRNA in human small-cell lung cancer. J Exp Med. 1985 May 1;161(5):1135–1151. doi: 10.1084/jem.161.5.1135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gomard E., Begue B., Sodoyer S., Maryanski J. L., Jordan B. R., Levy J. P. Murine cells expressing an HLA molecule are specifically lysed by HLA-restricted antiviral human T cells. Nature. 1986 Jan 9;319(6049):153–154. doi: 10.1038/319153a0. [DOI] [PubMed] [Google Scholar]
  9. Gomard E., Duprez V., Reme T., Colombani M. J., Levy J. P. Exclusive involvement of H-2Db or H-2Kd product in the interaction between T-killer lymphocytes and syngeneic H-2b or H-2d viral lymphomas. J Exp Med. 1977 Oct 1;146(4):909–922. doi: 10.1084/jem.146.4.909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Heidmann O., Rougeon F. Multiple sequences related to a constant-region kappa light chain gene in the rabbit genome. Cell. 1982 Mar;28(3):507–513. doi: 10.1016/0092-8674(82)90205-7. [DOI] [PubMed] [Google Scholar]
  11. Holden C. A., Shaw M., McKee P. H., Sanderson A. R., MacDonald D. M. Loss of membrane B2 microglobulin in eccrine porocarcinoma. Its association with the histopathologic and clinical criteria of malignancy. Arch Dermatol. 1984 Jun;120(6):732–735. [PubMed] [Google Scholar]
  12. Houghton A. N., Thomson T. M., Gross D., Oettgen H. F., Old L. J. Surface antigens of melanoma and melanocytes. Specificity of induction of Ia antigens by human gamma-interferon. J Exp Med. 1984 Jul 1;160(1):255–269. doi: 10.1084/jem.160.1.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hérin M., Lemoine C., Weynants P., Vessière F., Van Pel A., Knuth A., Devos R., Boon T. Production of stable cytolytic T-cell clones directed against autologous human melanoma. Int J Cancer. 1987 Mar 15;39(3):390–396. doi: 10.1002/ijc.2910390320. [DOI] [PubMed] [Google Scholar]
  14. Knuth A., Danowski B., Oettgen H. F., Old L. J. T-cell-mediated cytotoxicity against autologous malignant melanoma: analysis with interleukin 2-dependent T-cell cultures. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3511–3515. doi: 10.1073/pnas.81.11.3511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Knuth A., Wölfel T., Klehmann E., Boon T., Meyer zum Büschenfelde K. H. Cytolytic T-cell clones against an autologous human melanoma: specificity study and definition of three antigens by immunoselection. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2804–2808. doi: 10.1073/pnas.86.8.2804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Koller B. H., Orr H. T. Cloning and complete sequence of an HLA-A2 gene: analysis of two HLA-A alleles at the nucleotide level. J Immunol. 1985 Apr;134(4):2727–2733. [PubMed] [Google Scholar]
  17. Koo G. C., Goldberg C. L., Shen F. W. Inhibition of H-Y cell-mediated cytolysis by H-2Db antiserum. J Exp Med. 1979 Oct 1;150(4):1028–1032. doi: 10.1084/jem.150.4.1028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kripke M. L. Antigenicity of murine skin tumors induced by ultraviolet light. J Natl Cancer Inst. 1974 Nov;53(5):1333–1336. doi: 10.1093/jnci/53.5.1333. [DOI] [PubMed] [Google Scholar]
  19. Lampson L. A., Fisher C. A., Whelan J. P. Striking paucity of HLA-A, B, C and beta 2-microglobulin on human neuroblastoma cell lines. J Immunol. 1983 May;130(5):2471–2478. [PubMed] [Google Scholar]
  20. Lampson L. A., Levy R. Two populations of Ia-like molecules on a human B cell line. J Immunol. 1980 Jul;125(1):293–299. [PubMed] [Google Scholar]
  21. Livingston P. O., Shiku H., Bean M. A., Pinsky C. M., Oettgen H. F., Old L. J. Cell-mediated cytotoxicity for cultured autologous melanoma cells. Int J Cancer. 1979 Jul 15;24(1):34–44. doi: 10.1002/ijc.2910240107. [DOI] [PubMed] [Google Scholar]
  22. Maryanski J. L., Boon T. Immunogenic variants obtained by mutagenesis of mouse mastocytoma P815. IV. Analysis of variant-specific antigens by selection of antigen-loss variants with cytolytic T cell clones. Eur J Immunol. 1982 May;12(5):406–412. doi: 10.1002/eji.1830120509. [DOI] [PubMed] [Google Scholar]
  23. Masucci M. G., Torsteindottir S., Colombani J., Brautbar C., Klein E., Klein G. Down-regulation of class I HLA antigens and of the Epstein-Barr virus-encoded latent membrane protein in Burkitt lymphoma lines. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4567–4571. doi: 10.1073/pnas.84.13.4567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. McMichael A. J., Gotch F. M., Santos-Aguado J., Strominger J. L. Effect of mutations and variations of HLA-A2 on recognition of a virus peptide epitope by cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9194–9198. doi: 10.1073/pnas.85.23.9194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McMichael A. J., Parham P., Rust N., Brodsky F. A monoclonal antibody that recognizes an antigenic determinant shared by HLA A2 and B17. Hum Immunol. 1980 Sep;1(2):121–129. doi: 10.1016/0198-8859(80)90099-3. [DOI] [PubMed] [Google Scholar]
  26. Momburg F., Degener T., Bacchus E., Moldenhauer G., Hämmerling G. J., Möller P. Loss of HLA-A,B,C and de novo expression of HLA-D in colorectal cancer. Int J Cancer. 1986 Feb 15;37(2):179–184. doi: 10.1002/ijc.2910370203. [DOI] [PubMed] [Google Scholar]
  27. Momburg F., Ziegler A., Harpprecht J., Möller P., Moldenhauer G., Hämmerling G. J. Selective loss of HLA-A or HLA-B antigen expression in colon carcinoma. J Immunol. 1989 Jan 1;142(1):352–358. [PubMed] [Google Scholar]
  28. Mukherji B., MacAlister T. J. Clonal analysis of cytotoxic T cell response against human melanoma. J Exp Med. 1983 Jul 1;158(1):240–245. doi: 10.1084/jem.158.1.240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Müller C., Herbst H., Uchanska-Ziegler B., Ziegler A., Schunter F., Steiert I., Muller C., Wernet P. Characterization of a monoclonal anti-Bw4 antibody (Tü109): evidence for similar epitopes on the Bw4 and Bw6 antigens. Hum Immunol. 1985 Dec;14(4):333–349. doi: 10.1016/0198-8859(85)90241-1. [DOI] [PubMed] [Google Scholar]
  30. PREHN R. T., MAIN J. M. Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst. 1957 Jun;18(6):769–778. [PubMed] [Google Scholar]
  31. Parham P., Bodmer W. F. Monoclonal antibody to a human histocompatibility alloantigen, HLA-A2. Nature. 1978 Nov 23;276(5686):397–399. doi: 10.1038/276397a0. [DOI] [PubMed] [Google Scholar]
  32. Parham P., Brodsky F. M. Partial purification and some properties of BB7.2. A cytotoxic monoclonal antibody with specificity for HLA-A2 and a variant of HLA-A28. Hum Immunol. 1981 Dec;3(4):277–299. doi: 10.1016/0198-8859(81)90065-3. [DOI] [PubMed] [Google Scholar]
  33. Ruiter D. J., Bergman W., Welvaart K., Scheffer E., van Vloten W. A., Russo C., Ferrone S. Immunohistochemical analysis of malignant melanomas and nevocellular nevi with monoclonal antibodies to distinct monomorphic determinants of HLA antigens. Cancer Res. 1984 Sep;44(9):3930–3935. [PubMed] [Google Scholar]
  34. Schmitt-Verhulst A. M., Sachs D. H., Shearer G. M. Cell-mediated lympholysis of trinitrophenyl-modified autologous lymphocytes. Confirmation of genetic control of response to trinitrophenyl-modified H-2 antigens by the use of anti-H-2 and anti-Ia antibodies. J Exp Med. 1976 Jan 1;143(1):211–217. doi: 10.1084/jem.143.1.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Slovin S. F., Lackman R. D., Ferrone S., Kiely P. E., Mastrangelo M. J. Cellular immune response to human sarcomas: cytotoxic T cell clones reactive with autologous sarcomas. I. Development, phenotype, and specificity. J Immunol. 1986 Nov 1;137(9):3042–3048. [PubMed] [Google Scholar]
  36. Srivastava P. K., Old L. J. Individually distinct transplantation antigens of chemically induced mouse tumors. Immunol Today. 1988 Mar;9(3):78–83. doi: 10.1016/0167-5699(88)91269-8. [DOI] [PubMed] [Google Scholar]
  37. Taketani S., Krangel M. S., Pious D., Strominger J. L. Structural analysis of HLA-A2 antigen from immunoselected mutant 8.6.1: further definition of an HLA-A2-specific serological determinant. J Immunol. 1983 Dec;131(6):2935–2938. [PubMed] [Google Scholar]
  38. Tanaka K., Yoshioka T., Bieberich C., Jay G. Role of the major histocompatibility complex class I antigens in tumor growth and metastasis. Annu Rev Immunol. 1988;6:359–380. doi: 10.1146/annurev.iy.06.040188.002043. [DOI] [PubMed] [Google Scholar]
  39. Taramelli D., Fossati G., Mazzocchi A., Delia D., Ferrone S., Parmiani G. Classes I and II HLA and melanoma-associated antigen expression and modulation on melanoma cells isolated from primary and metastatic lesions. Cancer Res. 1986 Jan;46(1):433–439. [PubMed] [Google Scholar]
  40. Townsend A. R., Rothbard J., Gotch F. M., Bahadur G., Wraith D., McMichael A. J. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986 Mar 28;44(6):959–968. doi: 10.1016/0092-8674(86)90019-x. [DOI] [PubMed] [Google Scholar]
  41. Turbitt M. L., Mackie R. M. Loss of beta2 microglobulin from the cell surface of cutaneous malignant and premalignant lesions. Br J Dermatol. 1981 May;104(5):507–513. doi: 10.1111/j.1365-2133.1981.tb08164.x. [DOI] [PubMed] [Google Scholar]
  42. Uyttenhove C., Maryanski J., Boon T. Escape of mouse mastocytoma P815 after nearly complete rejection is due to antigen-loss variants rather than immunosuppression. J Exp Med. 1983 Mar 1;157(3):1040–1052. doi: 10.1084/jem.157.3.1040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Van Pel A., De Plaen E., Boon T. Selection of highly transfectable variant from mouse mastocytoma P815. Somat Cell Mol Genet. 1985 Sep;11(5):467–475. doi: 10.1007/BF01534840. [DOI] [PubMed] [Google Scholar]
  44. Vassart G., Georges M., Monsieur R., Brocas H., Lequarre A. S., Christophe D. A sequence in M13 phage detects hypervariable minisatellites in human and animal DNA. Science. 1987 Feb 6;235(4789):683–684. doi: 10.1126/science.2880398. [DOI] [PubMed] [Google Scholar]
  45. Versteeg R., Noordermeer I. A., Krüse-Wolters M., Ruiter D. J., Schrier P. I. c-myc down-regulates class I HLA expression in human melanomas. EMBO J. 1988 Apr;7(4):1023–1029. doi: 10.1002/j.1460-2075.1988.tb02909.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Whitwell H. L., Hughes H. P., Moore M., Ahmed A. Expression of major histocompatibility antigens and leucocyte infiltration in benign and malignant human breast disease. Br J Cancer. 1984 Feb;49(2):161–172. doi: 10.1038/bjc.1984.28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Yang S. Y., Morishima Y., Collins N. H., Alton T., Pollack M. S., Yunis E. J., Dupont B. Comparison of one-dimensional IEF patterns for serologically detectable HLA-A and B allotypes. Immunogenetics. 1984;19(3):217–231. doi: 10.1007/BF00364765. [DOI] [PubMed] [Google Scholar]
  48. Zinkernagel R. M., Doherty P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974 Apr 19;248(5450):701–702. doi: 10.1038/248701a0. [DOI] [PubMed] [Google Scholar]
  49. de Vries J. E., Spits H. Cloned human cytotoxic T lymphocyte (CTL) lines reactive with autologous melanoma cells. I. In vitro generation, isolation, and analysis to phenotype and specificity. J Immunol. 1984 Jan;132(1):510–519. [PubMed] [Google Scholar]

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