Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 May;84(9):1258–1264. doi: 10.1054/bjoc.2000.1744

Modulation of MUC1 mucin as an escape mechanism of breast cancer cells from autologous cytotoxic T-lymphocytes

K Kontani 1, O Taguchi 1, T Narita 1, M Izawa 1, N Hiraiwa 1, K Zenita 1, T Takeuchi 2, H Murai 2, S Miura 2, R Kannagi 1
PMCID: PMC2363877  PMID: 11336479

Abstract

MUC1 mucin is known to serve as a target molecule in the killing of breast cancer cells by cytotoxic T-lymphocytes (CTLs). We searched for a possible mechanism allowing tumour cells to escape from autologous CTLs. When the killing of breast cancer cells by autologous lymphocytes was examined in 26 patients with breast cancer, significant tumour cell lysis was observed in 8 patients, whereas virtually no autologous tumour cell lysis was detected in as many as 18 patients. In the patients who showed negligible tumour cell lysis, the autologous tumour cells expressed MUC1-related antigenic epitopes much more weakly than the tumour cells in the patients who exhibited strong cytotoxicity (significant statistically at P< 0.0005–0.0045), suggesting that the unresponsiveness of cancer cells to CTLs observed in these patients was mainly due to loss of MUC1 expression or modulation of its antigenicity. A breast cancer cell line, NZK-1, established from one of the cytotoxicity-negative patients, did not express MUC1 and was resistant to killing by CTLs, while control breast cancer cell lines expressing MUC-1 were readily killed by CTLs. Transfection of NZK-1 cells with MUC1 cDNA induced significant lysis by autologous T-lymphocytes. These results supported the importance of MUC1 mucin in autologous anti-tumour immunity, but suggested that the major escape mechanism of tumour cells from autologous T-lymphocytes is the loss and/or modulation of MUC1 antigenicity on tumour cells, which would limit the effectiveness of possible immunotherapy designed to target the MUC1 mucin. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: immunotherapy of cancer, breast cancer, mucin, carbohydrate determinants

Full Text

The Full Text of this article is available as a PDF (104.7 KB).

Selected References

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

  1. Acres B., Apostolopoulos V., Balloul J. M., Wreschner D., Xing P. X., Ali-Hadji D., Bizouarne N., Kieny M. P., McKenzie I. F. MUC1-specific immune responses in human MUC1 transgenic mice immunized with various human MUC1 vaccines. Cancer Immunol Immunother. 2000 Jan;48(10):588–594. doi: 10.1007/PL00006677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Agrawal B., Reddish M. A., Longenecker B. M. In vitro induction of MUC-1 peptide-specific type 1 T lymphocyte and cytotoxic T lymphocyte responses from healthy multiparous donors. J Immunol. 1996 Sep 1;157(5):2089–2095. [PubMed] [Google Scholar]
  3. Akagi J., Hodge J. W., McLaughlin J. P., Gritz L., Mazzara G., Kufe D., Schlom J., Kantor J. A. Therapeutic antitumor response after immunization with an admixture of recombinant vaccinia viruses expressing a modified MUC1 gene and the murine T-cell costimulatory molecule B7. J Immunother. 1997 Jan;20(1):38–47. doi: 10.1097/00002371-199701000-00004. [DOI] [PubMed] [Google Scholar]
  4. Bara J., Imberty A., Pérez S., Imai K., Yachi A., Oriol R. A fucose residue can mask the MUC-1 epitopes in normal and cancerous gastric mucosae. Int J Cancer. 1993 Jun 19;54(4):607–613. doi: 10.1002/ijc.2910540414. [DOI] [PubMed] [Google Scholar]
  5. Barnd D. L., Lan M. S., Metzgar R. S., Finn O. J. Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7159–7163. doi: 10.1073/pnas.86.18.7159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blockzjil A., Nilsson K., Nilsson O. Epitope characterization of MUC1 antibodies. Tumour Biol. 1998;19 (Suppl 1):46–56. doi: 10.1159/000056504. [DOI] [PubMed] [Google Scholar]
  7. Burchell J., Gendler S., Taylor-Papadimitriou J., Girling A., Lewis A., Millis R., Lamport D. Development and characterization of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin. Cancer Res. 1987 Oct 15;47(20):5476–5482. [PubMed] [Google Scholar]
  8. Burchell J., Wang D., Taylor-Papadimitriou J. Detection of the tumour-associated antigens recognized by the monoclonal antibodies HMFG-1 and 2 in serum from patients with breast cancer. Int J Cancer. 1984 Dec 15;34(6):763–768. doi: 10.1002/ijc.2910340605. [DOI] [PubMed] [Google Scholar]
  9. Böhm C. M., Mulder M. C., Zennadi R., Notter M., Schmitt-Gräff A., Finn O. J., Taylor-Papadimitriou J., Stein H., Clausen H., Riecken E. O. Carbohydrate recognition on MUC1-expressing targets enhances cytotoxicity of a T cell subpopulation. Scand J Immunol. 1997 Jul;46(1):27–34. doi: 10.1046/j.1365-3083.1996.d01-91.x. [DOI] [PubMed] [Google Scholar]
  10. Carmon L., El-Shami K. M., Paz A., Pascolo S., Tzehoval E., Tirosh B., Koren R., Feldman M., Fridkin M., Lemonnier F. A. Novel breast-tumor-associated MUC1-derived peptides: characterization in Db-/- x beta2 microglobulin (beta2m) null mice transgenic for a chimeric HLA-A2.1/Db-beta2 microglobulin single chain. Int J Cancer. 2000 Feb 1;85(3):391–397. [PubMed] [Google Scholar]
  11. Dai J., Allard W. J., Davis G., Yeung K. K. Effect of desialylation on binding, affinity, and specificity of 56 monoclonal antibodies against MUC1 mucin. Tumour Biol. 1998;19 (Suppl 1):100–110. doi: 10.1159/000056510. [DOI] [PubMed] [Google Scholar]
  12. Devine P. L., McGuckin M. A., Ramm L. E., Ward B. G., Pee D., Long S. Serum mucin antigens CASA and MSA in tumors of the breast, ovary, lung, pancreas, bladder, colon, and prostate. A blind trial with 420 patients. Cancer. 1993 Sep 15;72(6):2007–2015. doi: 10.1002/1097-0142(19930915)72:6<2007::aid-cncr2820720636>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  13. Finke J. H., Rayman P., Alexander J., Edinger M., Tubbs R. R., Connelly R., Pontes E., Bukowski R. Characterization of the cytolytic activity of CD4+ and CD8+ tumor-infiltrating lymphocytes in human renal cell carcinoma. Cancer Res. 1990 Apr 15;50(8):2363–2370. [PubMed] [Google Scholar]
  14. Gendler S. J., Lancaster C. A., Taylor-Papadimitriou J., Duhig T., Peat N., Burchell J., Pemberton L., Lalani E. N., Wilson D. Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin. J Biol Chem. 1990 Sep 5;265(25):15286–15293. [PubMed] [Google Scholar]
  15. Gendler S., Taylor-Papadimitriou J., Duhig T., Rothbard J., Burchell J. A highly immunogenic region of a human polymorphic epithelial mucin expressed by carcinomas is made up of tandem repeats. J Biol Chem. 1988 Sep 15;263(26):12820–12823. [PubMed] [Google Scholar]
  16. Gong J., Chen D., Kashiwaba M., Li Y., Chen L., Takeuchi H., Qu H., Rowse G. J., Gendler S. J., Kufe D. Reversal of tolerance to human MUC1 antigen in MUC1 transgenic mice immunized with fusions of dendritic and carcinoma cells. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6279–6283. doi: 10.1073/pnas.95.11.6279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hakomori S. Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Res. 1996 Dec 1;56(23):5309–5318. [PubMed] [Google Scholar]
  18. Hanisch F. G., Uhlenbruck G., Peter-Katalinic J., Egge H., Dabrowski J., Dabrowski U. Structures of neutral O-linked polylactosaminoglycans on human skim milk mucins. A novel type of linearly extended poly-N-acetyllactosamine backbones with Gal beta(1-4)GlcNAc beta(1-6) repeating units. J Biol Chem. 1989 Jan 15;264(2):872–883. [PubMed] [Google Scholar]
  19. Ho S. B., Shekels L. L., Toribara N. W., Kim Y. S., Lyftogt C., Cherwitz D. L., Niehans G. A. Mucin gene expression in normal, preneoplastic, and neoplastic human gastric epithelium. Cancer Res. 1995 Jun 15;55(12):2681–2690. [PubMed] [Google Scholar]
  20. Jerome K. R., Domenech N., Finn O. J. Tumor-specific cytotoxic T cell clones from patients with breast and pancreatic adenocarcinoma recognize EBV-immortalized B cells transfected with polymorphic epithelial mucin complementary DNA. J Immunol. 1993 Aug 1;151(3):1654–1662. [PubMed] [Google Scholar]
  21. Jerome K. R., Kirk A. D., Pecher G., Ferguson W. W., Finn O. J. A survivor of breast cancer with immunity to MUC-1 mucin, and lactational mastitis. Cancer Immunol Immunother. 1997 Jan;43(6):355–360. doi: 10.1007/s002620050344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Karanikas V., Hwang L. A., Pearson J., Ong C. S., Apostolopoulos V., Vaughan H., Xing P. X., Jamieson G., Pietersz G., Tait B. Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-MUC1 fusion protein. J Clin Invest. 1997 Dec 1;100(11):2783–2792. doi: 10.1172/JCI119825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kontani K., Taguchi O., Narita T., Hiraiwa N., Sawai S., Hanaoka J., Ichinose M., Tezuka N., Inoue S., Fujino S. Autologous dendritic cells or cells expressing both B7-1 and MUC1 can rescue tumor-specific cytotoxic T lymphocytes from MUC1-mediated apoptotic cell death. J Leukoc Biol. 2000 Aug;68(2):225–232. [PubMed] [Google Scholar]
  24. Kotera Y., Fontenot J. D., Pecher G., Metzgar R. S., Finn O. J. Humoral immunity against a tandem repeat epitope of human mucin MUC-1 in sera from breast, pancreatic, and colon cancer patients. Cancer Res. 1994 Jun 1;54(11):2856–2860. [PubMed] [Google Scholar]
  25. Lan M. S., Hollingsworth M. A., Metzgar R. S. Polypeptide core of a human pancreatic tumor mucin antigen. Cancer Res. 1990 May 15;50(10):2997–3001. [PubMed] [Google Scholar]
  26. Lloyd K. O., Burchell J., Kudryashov V., Yin B. W., Taylor-Papadimitriou J. Comparison of O-linked carbohydrate chains in MUC-1 mucin from normal breast epithelial cell lines and breast carcinoma cell lines. Demonstration of simpler and fewer glycan chains in tumor cells. J Biol Chem. 1996 Dec 27;271(52):33325–33334. doi: 10.1074/jbc.271.52.33325. [DOI] [PubMed] [Google Scholar]
  27. Magarian-Blander J., Ciborowski P., Hsia S., Watkins S. C., Finn O. J. Intercellular and intracellular events following the MHC-unrestricted TCR recognition of a tumor-specific peptide epitope on the epithelial antigen MUC1. J Immunol. 1998 Apr 1;160(7):3111–3120. [PubMed] [Google Scholar]
  28. Magarian-Blander J., Hughey R. P., Kinlough C., Poland P. A., Finn O. J. Differential expression of MUC1 on transfected cell lines influences its recognition by MUC1 specific T cells. Glycoconj J. 1996 Oct;13(5):749–756. doi: 10.1007/BF00702339. [DOI] [PubMed] [Google Scholar]
  29. Ogata S., Uehara H., Chen A., Itzkowitz S. H. Mucin gene expression in colonic tissues and cell lines. Cancer Res. 1992 Nov 1;52(21):5971–5978. [PubMed] [Google Scholar]
  30. Pecher G., Finn O. J. Induction of cellular immunity in chimpanzees to human tumor-associated antigen mucin by vaccination with MUC-1 cDNA-transfected Epstein-Barr virus-immortalized autologous B cells. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1699–1704. doi: 10.1073/pnas.93.4.1699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Potter H., Weir L., Leder P. Enhancer-dependent expression of human kappa immunoglobulin genes introduced into mouse pre-B lymphocytes by electroporation. Proc Natl Acad Sci U S A. 1984 Nov;81(22):7161–7165. doi: 10.1073/pnas.81.22.7161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Price M. R., Rye P. D., Petrakou E., Murray A., Brady K., Imai S., Haga S., Kiyozuka Y., Schol D., Meulenbroek M. F. Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin. San Diego, Calif., November 17-23, 1996. Tumour Biol. 1998;19 (Suppl 1):1–20. doi: 10.1159/000056500. [DOI] [PubMed] [Google Scholar]
  33. Rowse G. J., Tempero R. M., VanLith M. L., Hollingsworth M. A., Gendler S. J. Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model. Cancer Res. 1998 Jan 15;58(2):315–321. [PubMed] [Google Scholar]
  34. Samuel J., Budzynski W. A., Reddish M. A., Ding L., Zimmermann G. L., Krantz M. J., Koganty R. R., Longenecker B. M. Immunogenicity and antitumor activity of a liposomal MUC1 peptide-based vaccine. Int J Cancer. 1998 Jan 19;75(2):295–302. doi: 10.1002/(sici)1097-0215(19980119)75:2<295::aid-ijc20>3.0.co;2-b. [DOI] [PubMed] [Google Scholar]
  35. Siddiqui J., Abe M., Hayes D., Shani E., Yunis E., Kufe D. Isolation and sequencing of a cDNA coding for the human DF3 breast carcinoma-associated antigen. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2320–2323. doi: 10.1073/pnas.85.7.2320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Smyth M. J., Ortaldo J. R. Mechanisms of cytotoxicity used by human peripheral blood CD4+ and CD8+ T cell subsets. The role of granule exocytosis. J Immunol. 1993 Jul 15;151(2):740–747. [PubMed] [Google Scholar]
  37. Swallow D. M., Gendler S., Griffiths B., Corney G., Taylor-Papadimitriou J., Bramwell M. E. The human tumour-associated epithelial mucins are coded by an expressed hypervariable gene locus PUM. Nature. 1987 Jul 2;328(6125):82–84. doi: 10.1038/328082a0. [DOI] [PubMed] [Google Scholar]
  38. Takada A., Ohmori K., Yoneda T., Tsuyuoka K., Hasegawa A., Kiso M., Kannagi R. Contribution of carbohydrate antigens sialyl Lewis A and sialyl Lewis X to adhesion of human cancer cells to vascular endothelium. Cancer Res. 1993 Jan 15;53(2):354–361. [PubMed] [Google Scholar]
  39. Taylor-Papadimitriou J., Finn O. J. Biology, biochemistry and immunology of carcinoma-associated mucins. Immunol Today. 1997 Mar;18(3):105–107. doi: 10.1016/s0167-5699(97)01028-1. [DOI] [PubMed] [Google Scholar]
  40. Willsher P. C., Xing P. X., Clarke C. P., Ho D. W., McKenzie I. F. Mucin 1 antigens in the serum and bronchial lavage fluid of patients with lung cancer. Cancer. 1993 Nov 15;72(10):2936–2942. doi: 10.1002/1097-0142(19931115)72:10<2936::aid-cncr2820721013>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  41. Wright S. E., Kilinski L., Talib S., Lowe K. E., Burnside J. S., Wu J. Y., Dolby N., Dombrowski K. E., Lebkowski J. S., Philip R. Cytotoxic T lymphocytes from humans with adenocarcinomas stimulated by native MUC1 mucin and a mucin peptide mutated at a glycosylation site. J Immunother. 2000 Jan;23(1):2–10. doi: 10.1097/00002371-200001000-00002. [DOI] [PubMed] [Google Scholar]
  42. von Mensdorff-Pouilly S., Verstraeten A. A., Kenemans P., Snijdewint F. G., Kok A., Van Kamp G. J., Paul M. A., Van Diest P. J., Meijer S., Hilgers J. Survival in early breast cancer patients is favorably influenced by a natural humoral immune response to polymorphic epithelial mucin. J Clin Oncol. 2000 Feb;18(3):574–583. doi: 10.1200/JCO.2000.18.3.574. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES