Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1989 Sep 1;170(3):621–635. doi: 10.1084/jem.170.3.621

Suppression of class I human histocompatibility leukocyte antigen by c- myc is locus specific

PMCID: PMC2189425  PMID: 2788705

Abstract

The c-myc oncogene downregulates class I HLA expression in human melanoma. The major class I HLA antigens are encoded by three loci, A, B, and C, and we investigated whether these loci are suppressed equally by c-myc. In three melanoma cell lines with high c-myc expression, we analyzed mRNA, protein, and cell surface expression of the class I HLA antigens. Whereas the HLA-B locus expression was found to be strongly reduced, the HLA-A locus was expressed normally. Analysis of c-myc- transfected clones of two melanoma cell lines confirmed that c-myc preferentially suppresses the class I HLA-B locus. Immunohistochemical analysis of fresh melanoma lesions also showed that in the tumors the HLA-A loci are expressed normally, while on the majority of tumor cells no HLA-B antigen expression was found. This downregulation may have consequences for the recognition of malignant cells by tumor- infiltrating lymphocytes. Our results predict that HLA-B-restricted cytotoxic T cells will be unable to kill high c-myc-expressing melanoma cells.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

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

  1. Anichini A., Fossati G., Parmiani G. Clonal analysis of cytotoxic T-lymphocyte response to autologous human metastatic melanoma. Int J Cancer. 1985 May 15;35(5):683–689. doi: 10.1002/ijc.2910350518. [DOI] [PubMed] [Google Scholar]
  2. Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Bernards R., Houweling A., Schrier P. I., Bos J. L., Van der Eb A. J. Characterization of cells transformed by Ad5/Ad12 hybrid early region I plasmids. Virology. 1982 Jul 30;120(2):422–432. doi: 10.1016/0042-6822(82)90042-3. [DOI] [PubMed] [Google Scholar]
  6. Colby W. W., Chen E. Y., Smith D. H., Levinson A. D. Identification and nucleotide sequence of a human locus homologous to the v-myc oncogene of avian myelocytomatosis virus MC29. Nature. 1983 Feb 24;301(5902):722–725. doi: 10.1038/301722a0. [DOI] [PubMed] [Google Scholar]
  7. Cole M. D. The myc oncogene: its role in transformation and differentiation. Annu Rev Genet. 1986;20:361–384. doi: 10.1146/annurev.ge.20.120186.002045. [DOI] [PubMed] [Google Scholar]
  8. DeLellis R. A., Sternberger L. A., Mann R. B., Banks P. M., Nakane P. K. Immunoperoxidase technics in diagnostic pathology. Report of a workshop sponsored by the National Cancer Institute. Am J Clin Pathol. 1979 May;71(5):483–488. doi: 10.1093/ajcp/71.5.483. [DOI] [PubMed] [Google Scholar]
  9. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  10. Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Girdlestone J., Milstein C. Differential expression and interferon response of HLA class I genes in thymocyte lines and response variants. Eur J Immunol. 1988 Jan;18(1):139–143. doi: 10.1002/eji.1830180121. [DOI] [PubMed] [Google Scholar]
  12. Goodenow R. S., Vogel J. M., Linsk R. L. Histocompatibility antigens on murine tumors. Science. 1985 Nov 15;230(4727):777–783. doi: 10.1126/science.2997918. [DOI] [PubMed] [Google Scholar]
  13. Güssow D., Rein R. S., Meijer I., de Hoog W., Seemann G. H., Hochstenbach F. M., Ploegh H. L. Isolation, expression, and the primary structure of HLA-Cw1 and HLA-Cw2 genes: evolutionary aspects. Immunogenetics. 1987;25(5):313–322. doi: 10.1007/BF00404424. [DOI] [PubMed] [Google Scholar]
  14. Hayashi H., Tanaka K., Jay F., Khoury G., Jay G. Modulation of the tumorigenicity of human adenovirus-12-transformed cells by interferon. Cell. 1985 Nov;43(1):263–267. doi: 10.1016/0092-8674(85)90031-5. [DOI] [PubMed] [Google Scholar]
  15. Hersey P., MacDonald M., Schibeci S., Burns C. Clonal analysis of cytotoxic T lymphocytes (CTL) against autologous melanoma. Classification based on phenotype, specificity and inhibition by monoclonal antibodies to T cell structures. Cancer Immunol Immunother. 1986;22(1):15–23. doi: 10.1007/BF00205711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hui K., Grosveld F., Festenstein H. Rejection of transplantable AKR leukaemia cells following MHC DNA-mediated cell transformation. Nature. 1984 Oct 25;311(5988):750–752. doi: 10.1038/311750a0. [DOI] [PubMed] [Google Scholar]
  17. Hämmerling G. J., Klar D., Pülm W., Momburg F., Moldenhauer G. The influence of major histocompatibility complex class I antigens on tumor growth and metastasis. Biochim Biophys Acta. 1987 Nov 25;907(3):245–259. doi: 10.1016/0304-419x(87)90008-4. [DOI] [PubMed] [Google Scholar]
  18. Koller B. H., Sidwell B., DeMars R., Orr H. T. Isolation of HLA locus-specific DNA probes from the 3'-untranslated region. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5175–5178. doi: 10.1073/pnas.81.16.5175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kärre K., Ljunggren H. G., Piontek G., Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986 Feb 20;319(6055):675–678. doi: 10.1038/319675a0. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Mittal K. K., Mickey M. R., Singal D. P., Terasaki P. I. Serotyping for homotransplantation. 18. Refinement of microdroplet lymphocyte cytotoxicity test. Transplantation. 1968 Nov;6(8):913–927. doi: 10.1097/00007890-196811000-00006. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Neefjes J. J., Doxiadis I., Stam N. J., Beckers C. J., Ploegh H. L. An analysis of class I antigens of man and other species by one-dimensional IEF and immunoblotting. Immunogenetics. 1986;23(3):164–171. doi: 10.1007/BF00373817. [DOI] [PubMed] [Google Scholar]
  24. Neefjes J. J., Ploegh H. L. Allele and locus-specific differences in cell surface expression and the association of HLA class I heavy chain with beta 2-microglobulin: differential effects of inhibition of glycosylation on class I subunit association. Eur J Immunol. 1988 May;18(5):801–810. doi: 10.1002/eji.1830180522. [DOI] [PubMed] [Google Scholar]
  25. Rebaï N., Malissen B. Structural and genetic analyses of HLA class I molecules using monoclonal xenoantibodies. Tissue Antigens. 1983 Aug;22(2):107–117. doi: 10.1111/j.1399-0039.1983.tb01176.x. [DOI] [PubMed] [Google Scholar]
  26. Rein R. S., Seemann G. H., Neefjes J. J., Hochstenbach F. M., Stam N. J., Ploegh H. L. Association with beta 2-microglobulin controls the expression of transfected human class I genes. J Immunol. 1987 Feb 15;138(4):1178–1183. [PubMed] [Google Scholar]
  27. Rosenberg S. A., Packard B. S., Aebersold P. M., Solomon D., Topalian S. L., Toy S. T., Simon P., Lotze M. T., Yang J. C., Seipp C. A. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988 Dec 22;319(25):1676–1680. doi: 10.1056/NEJM198812223192527. [DOI] [PubMed] [Google Scholar]
  28. Schrier P. I., Bernards R., Vaessen R. T., Houweling A., van der Eb A. J. Expression of class I major histocompatibility antigens switched off by highly oncogenic adenovirus 12 in transformed rat cells. 1983 Oct 27-Nov 2Nature. 305(5937):771–775. doi: 10.1038/305771a0. [DOI] [PubMed] [Google Scholar]
  29. Smith M. E., Bodmer W. F., Bodmer J. G. Selective loss of HLA-A,B,C locus products in colorectal adenocarcinoma. Lancet. 1988 Apr 9;1(8589):823–824. doi: 10.1016/s0140-6736(88)91682-0. [DOI] [PubMed] [Google Scholar]
  30. Stam N. J., Spits H., Ploegh H. L. Monoclonal antibodies raised against denatured HLA-B locus heavy chains permit biochemical characterization of certain HLA-C locus products. J Immunol. 1986 Oct 1;137(7):2299–2306. [PubMed] [Google Scholar]
  31. Taniguchi K., Kärre K., Klein G. Lung colonization and metastasis by disseminated B16 melanoma cells: H-2 associated control at the level of the host and the tumor cell. Int J Cancer. 1985 Oct 15;36(4):503–510. doi: 10.1002/ijc.2910360415. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Wallich R., Bulbuc N., Hämmerling G. J., Katzav S., Segal S., Feldman M. Abrogation of metastatic properties of tumour cells by de novo expression of H-2K antigens following H-2 gene transfection. Nature. 1985 May 23;315(6017):301–305. doi: 10.1038/315301a0. [DOI] [PubMed] [Google Scholar]
  34. Weber J. S., Jay G., Tanaka K., Rosenberg S. A. Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection. J Exp Med. 1987 Dec 1;166(6):1716–1733. doi: 10.1084/jem.166.6.1716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. van Duinen S. G., Ruiter D. J., Broecker E. B., van der Velde E. A., Sorg C., Welvaart K., Ferrone S. Level of HLA antigens in locoregional metastases and clinical course of the disease in patients with melanoma. Cancer Res. 1988 Feb 15;48(4):1019–1025. [PubMed] [Google Scholar]
  37. van der Eb A. J., Graham F. L. Assay of transforming activity of tumor virus DNA. Methods Enzymol. 1980;65(1):826–839. doi: 10.1016/s0076-6879(80)65077-0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES