Skip to main content
SpringerLink
Log in

Reduced T-Cell and Dendritic Cell Function Is Related to Cyclooxygenase-2 Overexpression and Prostaglandin E2 Secretion in Patients With Breast Cancer

  • Original Articles
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background: In several neoplastic diseases, including breast cancer, immunosuppression correlates with disease stage, progression, and outcome. Thus, thorough analysis of immune parameters in breast cancer patients may be beneficial in designing effective anticancer immune-based therapies.

Methods: We investigated dendritic cell and T-cell function in breast cancer patients at various stages of the disease and in age-matched controls. We also evaluated cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) levels within the tumor milieu and in the circulation.

Results: T cells from cancer patients showed decreased proliferation in response to CD3 antibody stimulation. Analysis of T-cell helper type 1 and 2 cytokines revealed reduced levels of interferon-γ, tumor necrosis factor-α, interleukin (IL)-12, and IL-2 and increased levels of IL-10 and IL-4. Dendritic cells from these patients showed significantly reduced expression of co-stimulatory molecules (B7 and CD40) and demonstrated reduced phagocytic ability, reduced antigen presentation to T cells, and reduced ability to mature in response to lipopolysaccharide. Data revealed increased synthesis of PGE2, an immune suppressor, along with increased expression of COX-2, a key regulator of PGE2 synthesis.

Conclusions: COX-2–induced PGE2 may contribute to immunosuppression and may directly block antitumor immunity while promoting tumor growth, providing us with the rationale for using COX-2 inhibition combined with immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Staveley-O’Carroll K, Sotomayor E, Montgomery J, et al. Induction of antigen-specific T cell anergy: an early event in the course of tumor progression. Proc Natl Acad Sci U S A 1998;95:1178–83.

    Article  CAS  PubMed  Google Scholar 

  2. Pardoll D. Does the immune system see tumors as foreign or self? Ann Rev Immunol 2003;21:807–39.

    Google Scholar 

  3. Finke J, Ferrone S, Frey A, Mufson A, Ochoa A. Where have all the T cells gone? Mechanisms of immune evasion by tumors. Immunol Today 1999;20:158–60.

    Google Scholar 

  4. Keilholz U, Weber J, Finke JH, et al. Immunologic monitoring of cancer vaccine therapy: results of a workshop sponsored by the Society for Biological Therapy. J Immunother 2002;25:97–138.

    Google Scholar 

  5. Goto S, Sato M, Kaneko R, Itoh M, Sato S, Takeuchi S. Analysis of Th1 and Th2 cytokine production by peripheral blood mononuclear cells as a parameter of immunological dysfunction in advanced cancer patients. Cancer Immunol Immunother 1999;48:435–42.

    Google Scholar 

  6. Enk AH, Jonuleit H, Saloga J, Knop J. Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer 1997;73:309–16.

    Google Scholar 

  7. Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP. Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 1997;3:483–90.

    CAS  PubMed  Google Scholar 

  8. Almand B, Resser JR, Lindman B, et al. Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 2000;6:1755–66.

    CAS  PubMed  Google Scholar 

  9. Singh B, Lucci A. Role of cyclooxygenase-2 in breast cancer. J Surg Res 2002;108:173–9.

    Google Scholar 

  10. Singh-Ranger G, Mokbel K. The role of cyclooxygenase-2 (COX-2) in breast cancer, and implications of COX-2 inhibition. Eur J Surg Oncol 2002;28:729–37.

    CAS  PubMed  Google Scholar 

  11. Half E, Tang XM, Gwyn K, Sahin A, Wathen K, Sinicrope FA. Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. Cancer Res 2002;62:1676–81.

    CAS  PubMed  Google Scholar 

  12. Herschman HR. Regulation of prostaglandin synthase-1 and prostaglandin synthase-2. Cancer Metastasis Rev 1994;13:241–56.

    Google Scholar 

  13. Herschman HR. Prostaglandin synthase 2. Biochim Biophys Acta 1996;1299:125–40.

    Google Scholar 

  14. Liu CH, Chang SH, Narko K, et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 2001;276:18563–9.

    Article  CAS  PubMed  Google Scholar 

  15. Munkarah AR, Morris R, Baumann P, et al. Effects of prostaglandin E(2) on proliferation and apoptosis of epithelial ovarian cancer cells. J Soc Gynecol Invest 2002;9:168–73.

    Google Scholar 

  16. Amano H, Hayashi I, Endo H, et al. Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med 2003;197:221–32.

    Google Scholar 

  17. Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D, Tarnawski AS. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 2002;8:289–93.

    Article  CAS  PubMed  Google Scholar 

  18. Harizi H, Juzan M, Pitard V, Moreau JF, Gualde N. Cyclooxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulates dendritic cell functions. J Immunol 2002;168:2255–63.

    Google Scholar 

  19. Sharma S, Stolina M, Lin Y, et al. T cell-derived IL-10 promotes lung cancer growth by suppressing both T cell and APC function. J Immunol 1999;163:5020–8.

    Google Scholar 

  20. Stolina M, Sharma S, Lin Y, et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 2000;164:361–70.

    CAS  PubMed  Google Scholar 

  21. Lanzavecchia A, Sallusto F. Dynamics of T lymphocyte responses: intermediates, effectors, and memory cells. Science 2000;290:92–7.

    Google Scholar 

  22. Pradelles P, Grassi J, Maclouf J. Enzyme immunoassays of eicosanoids using acetylcholine esterase as label: an alternative to radioimmunoassay. Anal Chem 1985;57:1170–3.

    Google Scholar 

  23. Maxey KM, Maddipati KR, Birkmeier J. Interference in enzyme immunoassays. J Clin Immunoassay 1992;15:116–20.

    Google Scholar 

  24. Goodwin JS, Bankhurst AD, Messner RP. Suppression of human T-cell mitogenesis by prostaglandin. Existence of a prostaglandin-producing suppressor cell. J Exp Med 1977;146:1719–34.

    Google Scholar 

  25. Kabashima K, Sakata D, Nagamachi M, Miyachi Y, Inaba K, Narumiya S. Prostaglandin E2-EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells. Nat Med 2003;9:744–9.

    Google Scholar 

  26. Finke JH, Zea AH, Stanley J, et al. Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res 1993;53:5613–6.

    Google Scholar 

  27. Ghosh P, Sica A, Young HA, et al. Alterations in NF kappa B/Rel family proteins in splenic T-cells from tumor-bearing mice and reversal following therapy. Cancer Res 1994;54:2969–72.

    Google Scholar 

  28. Appleman LJ, Tzachanis D, Grader-Beck T, van Puijenbroek AA, Boussiotis VA. Helper T cell anergy: from biochemistry to cancer pathophysiology and therapeutics. J Mol Med 2001;78:673–83.

    Article  CAS  PubMed  Google Scholar 

  29. Schmielau J, Finn OJ. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. Cancer Res 2001;61:4756–60.

    CAS  PubMed  Google Scholar 

  30. Schmielau J, Nalesnik MA, Finn OJ. Suppressed T-cell receptor zeta chain expression and cytokine production in pancreatic cancer patients. Clin Cancer Res 2001;7(3 Suppl):933s–939s.

    CAS  PubMed  Google Scholar 

  31. Nieland JD, Loviscek K, Kono K, et al. PBLs of early breast carcinoma patients with a high nuclear grade tumor unlike PBLs of cervical carcinoma patients do not show a decreased TCR zeta expression but are functionally impaired. J Immunother 1998;21:317–22.

    Google Scholar 

  32. Lucey DR, Clerici M, Shearer GM. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev 1996;9:532–62.

    Google Scholar 

  33. Onishi T, Ohishi Y, Goto H, Tomita M, Abe K. An assessment of the immunological status of patients with renal cell carcinoma based on the relative abundance of T-helper 1- and −2 cytokine-producing CD4+ cells in peripheral blood. BJU Int 2001;87:755–9.

    Google Scholar 

  34. Duan Z, Feller AJ, Penson RT, Chabner BA, Seiden MV. Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-resistant phenotype. Clin Cancer Res 1999;5:3445–53.

    Google Scholar 

  35. Kunz M, Toksoy A, Goebeler M, Engelhardt E, Brocker E, Gillitzer R. Strong expression of the lymphoattractant C-X-C chemokine Mig is associated with heavy infiltration of T cells in human malignant melanoma. J Pathol 1999;189:552–8.

    Article  CAS  PubMed  Google Scholar 

  36. Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu Rev Immunol 1997;15:675–705.

    Article  CAS  PubMed  Google Scholar 

  37. Groux H, Bigler M, de Vries JE, Roncarolo MG. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 1996;184:19–29.

    Google Scholar 

  38. Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol 1998;16:137–61.

    Article  CAS  PubMed  Google Scholar 

  39. McCoy JM, Wicks JR, Audoly LP. The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis. J Clin Invest 2002;110:651–8.

    Google Scholar 

  40. Menetrier-Caux C, Montmain G, Dieu MC, et al. Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 1998;92:4778–91.

    Google Scholar 

  41. Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 2000;192:1213–22.

    Article  CAS  PubMed  Google Scholar 

  42. Bell D, Chomarat P, Broyles D, et al. In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 1999;190:1417–26.

    Article  CAS  PubMed  Google Scholar 

  43. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Ann Rev Immunol 2003;21:685–711.

    Google Scholar 

  44. Roper RL, Phipps RP. Prostaglandin E2 regulation of the immune response. Adv Prostaglandin Thromboxane Leukot Res 1994;22:101–11.

    Google Scholar 

  45. Snijdewint FG, Kalinski P, Wierenga EA, Bos JD, Kapsenberg ML. Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J Immunol 1993;150:5321–9.

    Google Scholar 

  46. Misra N, Selvakumar M, Singh S, et al. Monocyte derived IL 10 and PGE2 are associated with the absence of Th 1 cells and in vitro T cell suppression in lepromatous leprosy. Immunol Lett 1995;48:123–8.

    Google Scholar 

  47. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med 1996;184:747–52.

    Article  Google Scholar 

  48. Kalinski P, Vieira PL, Schuitemaker JH, de Jong EC, Kapsenberg ML. Prostaglandin E(2) is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer. Blood 2001;97:3466–9.

    Article  CAS  PubMed  Google Scholar 

  49. Morecki S, Yacovlev E, Gelfand Y, Trembovler V, Shohami E, Slavin S. Induction of antitumor immunity by indomethacin. Cancer Immunol Immunother 2000;48:613–20.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Surgery, Mayo Clinic College of Medicine, Scottsdale, Arizona

    Barbara A. Pockaj MD, Gargi D. Basu PhD, Latha B. Pathangey MS, Richard J. Gray MD, Jose L. Hernandez BA, Sandra J. Gendler PhD & Pinku Mukherjee PhD

  2. Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Scottsdale, Arizona

    Gargi D. Basu PhD, Latha B. Pathangey MS, Jose L. Hernandez BA, Sandra J. Gendler PhD & Pinku Mukherjee PhD

  3. Biostatistics, Mayo Clinic College of Medicine, Scottsdale, Arizona

    Jose L. Hernandez BA

  4. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 13400 E. Shea Blvd., Scottsdale, AZ, 85259

    Pinku Mukherjee PhD

Authors
  1. Barbara A. Pockaj MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gargi D. Basu PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Latha B. Pathangey MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard J. Gray MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jose L. Hernandez BA
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandra J. Gendler PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pinku Mukherjee PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pinku Mukherjee PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pockaj, B.A., Basu, G.D., Pathangey, L.B. et al. Reduced T-Cell and Dendritic Cell Function Is Related to Cyclooxygenase-2 Overexpression and Prostaglandin E2 Secretion in Patients With Breast Cancer. Ann Surg Oncol 11, 328–339 (2004). https://doi.org/10.1245/ASO.2004.05.027

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1245/ASO.2004.05.027

Key Words

Search

Navigation