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Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2

Abstract

A number of adenocarcinomas abundantly express and secrete underglycosylated MUC1 mucin. Underglycosylation exposes tandem repeat peptide sequences on cancer-associated MUC1 mucin that are normally cryptic. High levels of MUC1 mucin are correlated with a poor prognosis and immunosuppression in adenocarcinoma patients. In this report we show that cancer-associated MUC1 mucin, affinity-purified from ascites fluids of cancer patients, and synthetic tandem repeats of MUC1 mucin core peptide can suppress human T-cell proliferative responses. This MUC1 mucin-induced suppression of T-cell responses can be reversed by the addition of exogenous IL-2 or anti-CD28 monoclonal antibody. These results are consistent with other studies showing that lymphocytes present in the vicinity of tumor cells are anergic and can be reactivated with exogenous interleukin-2. Overcoming MUC1 mucin-induced immunosuppression with IL-2 combined with active specific immunotherapy might be an effective immunotherapeutic strategy against human adenocarcinomas.

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References

  1. Hanisch, H.-G. et al. Structure of O-linked polyacrosaminoglycans on human skim milk mucin: A novel type of linearly extended poly-N-acetyl-lactosamine backbones with Gal β (1-4) GlcNAcb (1-6) repeating units. J. Biol. Chem. 264, 872–883 (1989).

    CAS  PubMed  Google Scholar 

  2. Gendler, S., Taylor-Papadimitriou, J., Duhig, T., Rothbard, J. & Burchell, J.A. A highly immunogenic region of a human polymorphic epithelial mucin expressed by carcinomas is made up of tandem repeats. J. Biol. Chem. 263, 12820 (1988).

  3. Siddiqui, J. et al. Isolation and sequencing of a cDNA coding for the human DF3 breast carcinoma-associated antigen. Proc. Natl. Acad. Sci. USA 85, 2320 (1988).

    Article  CAS  Google Scholar 

  4. Parry, G., Beck, J.C., Moss, L., Bartley, J. & Ojakian, G.K. Determination of apical membrane polarity in mammary epithelial cell cultures: The role of cell-cell, cell-substratum, and membrane-cytoskeleton interactions. Exp. Cell Res. 188, 302–311 (1990).

    Article  CAS  Google Scholar 

  5. Zotter, S., Hageman, P.C., Lossnitzer, A., Mooi, W.J. & Hilgers, J. Tissue and tumor distribution of human polymorphic epithelial mucin. Cancer Rev. 11, 55–101 (1988).

    Google Scholar 

  6. Burchell, J. et al. Development and characterization of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin. Cancer Res. 47, 5476–5482 (1987).

    CAS  PubMed  Google Scholar 

  7. Bresalier, R.S. et al. Mucin production by human colonic carcinoma cells correlates with their metastatic potential in animal models of colon cancer metastasis. J. Clin. Invest. 87, 1037–1045 (1991).

    Article  CAS  Google Scholar 

  8. Kobayashi, H., Terao, T. & Kawashima, Y. Serum sialyl Tn as an independent predictor of poor prognosis in patients with epithelial ovarian cancer. J. Clin. Oncol. 10, 95–101 (1992).

    Article  CAS  Google Scholar 

  9. Nakamori, S., Ota, D.M., Cleary, K.R., Shirotani, K. & Irimura, T. MUC-1 mucin expression as a marker of progression and metastasis of human colorectal carcinoma. Castroenterology 106, 353–361 (1994).

    Article  CAS  Google Scholar 

  10. Berruti, A. et al. Prognostic value in predicting overall survival of two mucinous markers: CA 15-3 and CA 125 in breast cancer patients at first relapse of disease. Eur. J. Cancer. 30A, 2082–2084 (1994).

    Article  CAS  Google Scholar 

  11. McGuckin, M.A., Walsh, M.D., Hohn, B.G., Ward, B.G. & Wright, R.G. Prognostic significance of MUC-1 epithelial mucin expression in breast cancer. Hum. Pathol. 26, 432–439 (1995).

    Article  CAS  Google Scholar 

  12. Hilkens, J. et al. Is episialin/MUC-1 involved in breast cancer progression? Cancer Lett. 90, 27–33 (1995).

    Article  CAS  Google Scholar 

  13. Fung, P.Y.S. & Longenecker, B.M. Specific immunosuppressive activity of epiglycanin, a mucin-like glycoprotein secreted by a murine mammary adenocarcinoma (TA3-HA). Cancer Res. 51, 1170–1176 (1991).

    CAS  PubMed  Google Scholar 

  14. MacLean, G.D., Reddish, M.A. & Longenecker, B.M. Prognostic significance of preimmunotherapy serum CA27. 29 (MUC-1) mucin level following active specific immunotherapy of metastatic adenocarcinoma patients. J. Immunother. 19, 70–78 (1997).

    Article  Google Scholar 

  15. Reddish, M.A., Maclean, G.D., Poppema, S.A., Berg, A. & Longenecker, B.M. Preimmunotherapy serum CA27. 29 (MUC-1) mucin level and CD69+ lymphocytes correlate with effects of theratope sialyl-Tn-KLH cancer vaccine in active specific immunotherapy. Cancer Immunol. Immunother. 42, 303–309 (1996).

    Article  CAS  Google Scholar 

  16. Regimbald, L.H. et al. The breast cancer mucin MUC1 as a novel adhesion ligand for endothelial intercellular adhesion molecule 1 in breast cancer. Cancer Res. 56, 4244–4249 (1996).

    CAS  PubMed  Google Scholar 

  17. Gimmi, C.D. et al. Breast cancer-associated antigen, DF3/MUC1, induces apoptosis of activated human T cells. Nature Med. 2, 1367–1370 (1996).

    Article  CAS  Google Scholar 

  18. Berd, D. et al. Activation markers on T cells infiltrating melanoma metastases after therapy with dinitrophenyl-conjugated vaccine. Cancer Immunol. Immunother. 39, 141–149 (1994).

    Article  CAS  Google Scholar 

  19. Alexander, R.B. et al. Helper T cells infiltrating human renal cell carcinomas have the phenotype of the activated memory-like T lymphocytes. J. Immunother. 17, 39–46 (1995).

    Article  CAS  Google Scholar 

  20. Coventry, B.J. et al. Lack of IL-2 cytokine expression despite IL-2 messenger RNA transcription in tumor infiltrating lymphocytes in primary human breast carcinoma. J. Immunol. 156, 3486–3492 (1996).

    CAS  PubMed  Google Scholar 

  21. Kurosaka, A. et al. A monoclonal antibody that recognizes a cluster of a disaccharide, NeuAca2 to 6GalNAc, in mucin-type glycoproteins. J. Biol. Chem. 262, 8724–8726 (1988).

    Google Scholar 

  22. Chan, D.W. et al. Use of Truquant® BR™ RIA for the early detection of breast cancer recurrence in patients with stage II and stage III disease. J. Clin. Oncol. 15, 2322–2328 (1997).

    Article  CAS  Google Scholar 

  23. Sad, S. & Mosmann, T.R. Interleukin (IL) 4, in the absence of antigen stimulation, induces an anergy-like state in differentiated CD8+ TC1 cells: Loss of IL-2 synthesis and autonomous proliferation but retention of cytotoxicity and synthesis of other cytokines. J. Exp. Med. 182, 1505–1515 (1995).

    Article  CAS  Google Scholar 

  24. Luzzati, A.L. et al. Interferon-gamma (IFN-γ) can counteract the in vitro inhibitory effect of an HIV p24 immunosuppressive heptapeptide. Clin. Exp. Immunol. 105, 403–408 (1996).

    Article  CAS  Google Scholar 

  25. Brunner, T. et al. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373, 441–444 (1995).

    Article  CAS  Google Scholar 

  26. Barinaga, M. Life-death balance within the cell. Science 274, 724 (1996).

    Article  CAS  Google Scholar 

  27. Beverly, B., Kang, S-M., Lenardo, M.J. & Schwartz, R.H. Reversal of in vitro T cell anergy by IL-2 stimulation. Int. Immunol. 4, 661–671 (1992).

    Article  CAS  Google Scholar 

  28. Mayumi, H., Umesue, M. & Nomoto, K. Cyclophosphamide-induced immunological tolerance: An overview. Immunobiology 195(2), 129–139 (1996).

    Article  CAS  Google Scholar 

  29. Fontenot, J.D. et al. Biophysical characterization of one-, two-, and three- tandem repeats of human mucin (MUC-1) protein core. Cancer Res. 53, 5386–5393 (1993).

    CAS  PubMed  Google Scholar 

  30. Bohmig, G.A., Kovarik, J., Holter, W., Pohanka, E. & Zlabinger, G.J. Specific down-regulation of proliferative T cell alloresponsiveness by interference with CD2/LFA-3 and LFA-1/ICAM-1 in vitro. J. Immunol. 152, 3720–3728 (1994).

    CAS  PubMed  Google Scholar 

  31. Ding, L. et al. Immunogenicity of synthetic peptides related to the core peptide sequence encoded by the human MUC1 mucin gene: Effect of immunization on the growth of murine mammary adenocarcinoma cells transfected with the human MUC1 gene. Cancer Immunol. Immunother. 36, 9–17 (1992).

    Article  Google Scholar 

  32. Apostolopoulos, V., Loveland, B.E., Pietersz, G.A. & McKenzie, I.F.C. CTL in mice immunized with human mucin 1 are MHC-restricted. J. Immunol. 155, 5089–5095 (1995).

    CAS  PubMed  Google Scholar 

  33. Agrawal, B., Reddish, M.A. & Longenecker, B.M. In vitro induction of MUC-1 peptide-specific type 1 T lymphocytes and cytotoxic T lymphocytes responses from healthy multiparous donors. J. Immunol. 157, 2089–2095 (1996).

    CAS  PubMed  Google Scholar 

  34. Berd, D., Mastrangelo, M.J., Engstrom, P.F., Paul, A. & Maguire, H. Augmentation of the human immune response by cyclophosphamide. Cancer Res. 42, 4862–4866 (1982).

    CAS  PubMed  Google Scholar 

  35. Berd, D. & Mastrangelo, M.J. Effect of low dose cyclophosphamide on the immune system of cancer patients: Depletion of CD4+, 2H4+ suppressor-inducer T cells. Cancer Res. 48, 1671–1675 (1988).

    CAS  PubMed  Google Scholar 

  36. Fung, P.Y.S., Madej, M., Koganty, R. & Longenecker, B.M. Active specific immunotherapy of a murine mammary adenocarcinoma using a synthetic tumor-associated glycoconjugate. Cancer Res. 50, 4308–4314 (1990).

    CAS  PubMed  Google Scholar 

  37. Agrawal, B., Reddish, M. & Longenecker, B.M. CD30 expression on human CD8+ T cells isolated from peripheral blood lymphocytes of normal donors. J. Immunol. 157, 3229–3234 (1996).

    CAS  PubMed  Google Scholar 

  38. Reddish, M., Black, N., Almeida, A., Suresh, M.R. & Longenecker, B.M. Epitope mapping of MAb B27.29 within the peptide core of the malignant breast carcinoma-associated mucin antigen coded for the human MUC1 gene. J. Tumor Marker Oncol. 7, 19–27 (1992).

    Google Scholar 

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Agrawal, B., Krantz, M., Reddish, M. et al. Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2. Nat Med 4, 43–49 (1998). https://doi.org/10.1038/nm0198-043

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