Indomethacin, Prostaglandin, and Immune Regulation in Melanoma

  • Charles M. Balch
  • Arabella B. Tilden


Melanoma patients exhibit decreased immunocompetence as measured by a variety of in vitro and in vivo immunological responses (Golub et al.,1974; Eilber et al.,1975; Zembala et al.,1977). It has been assumed that this decreased immunocompetence is due to a deficiency of effector-cell function (e.g., antibody-forming B lymphocytes, cytotoxic T lymphocytes). Such a concept led to a strategy of immunotherapy; manipulations with the goal of stimulating the immune system to correct the deficit. However, information obtained in recent years has demonstrated that the tempo, intensity, and even the choice of effector cells may be regulated in part by suppressor cells and by helper cells (also called amplifying cells, accessory cells, or inducer cells). Thus, the observation that melanoma patients exhibit decreased immunocompetence should be examined in the context of helper and suppressor lymphocytes or macrophages or both, for the immunosuppressed state in some patients might be due to too little “help” or too much suppression. Furthermore, this concept may partially explain the failure of immunotherapy to improve survival rates, since there is some experimental evidence that immunotherapy agents may have a dual effect by stimulating both effector cells and suppressor cells with the result that there is no net change in immune balance.


Melanoma Patient Suppressor Cell Immune Regulation Natural Killer Cell Activity Bacillus Calmette Guerin 
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  1. Balch, C. M., Dougherty, P. A., Dagg, M. K., Diethelm, A. G., and Lawton, A. R., 1977, Detection of human T cells using anti-monkey thymocyte antisera, Clin. Immunol. Immunopathol. 8: 448.PubMedCrossRefGoogle Scholar
  2. Balch, C. M., Murad, T. M., Soong, S., Ingalls, A. L., Halpern, N. B., and Maddox, W. A., 1978, A multi-factorial analysis of melanoma. I. Prognostic histopathological features comparing Clark’s and Breslow’s staging methods, Ann. Surg. 188: 732.PubMedCrossRefGoogle Scholar
  3. Balch, C. M., Murad, T. M., Soong, S. J., Ingalls, A. L., Richards, P. C., and Maddox, W. A., 1979a, Tumor thickness as a guide to surgical management of clinical stage I melanoma patients, Cancer 43: 883.CrossRefGoogle Scholar
  4. Balch, C. M., Soong, S. J., Murad, T. M., Ingalls, A. L., and Maddox, W. A., 1979b, A multifactorial analysis“ of melanoma. II. Prognostic factors in patients with State I (localized) melanoma, Surgery 86:343.Google Scholar
  5. Balch, C. M., Dougherty, P. A., and Tilden, A. B., 1981a, Excessive prostaglandin E2 production by suppressor cells in head and neck cancer patients, Proceedings ASCO/AACR (in Apress).Google Scholar
  6. Balch, C. M., Soong, S. J., Murad, T. M., Ingalls, A. L., and Maddox, W. A., 1979b, A multifactorial analysis of melanoma. II. Prognostic factors in patients with Stage I (localized) melanoma, Surgery 86: 343.Google Scholar
  7. Balch, C. M., Dougherty, P. A., and Tilden, A. B., 1981a, Excessive prostaglandin E2 production by suppressor cells in head and neck cancer patients, Proceedings ASCO/AACR 23: 310.Google Scholar
  8. Balch, C. M., Dougherty, P. A., and Tilden, A. B., 1981a, cell activity in man, J. Exp. Med. 146:1455.Google Scholar
  9. Braun, W., and Ishizuka, M., 1971, Antibody formation: Reduced responses after administration of excessive amounts of nonspecific stimulators, Proc. Natl. Acad. Sci. U.S.A. 68: 114.CrossRefGoogle Scholar
  10. Broder, S., Humphrey, R., Durm, M., Blackman, M., Meade, B., Goldman, C., Strober, W., and Waldmann, T., 1975, Impaired synthesis of polyclonal (non-paraprotein) immunoglobulins by circulating lymphocytes from patients with multiple myeloma—role of suppressor cells, N. Engl. J. Med. 293: 887.PubMedCrossRefGoogle Scholar
  11. Broder, S., Poplack, D., Whang-Peng, J., Durm, M., Goldman, C., Muul, L. and Waldmann, T. A., 1978, Characterization of a suppressor-cell leukemia: Evidence for the requirement of an interaction of two T cells in the development of human suppressor-effector cells, N. Engl. J. Med. 298: 66.PubMedCrossRefGoogle Scholar
  12. Brunda, M. J., Herberman, R. B., and Holden, H. T., 1980, Inhibition of murine natural killer cell activity by prostaglandins, J. Immunol. 124: 2682.PubMedGoogle Scholar
  13. Darrow, T. L., and Tomar, R. H., 1980, Prostaglandin-mediated regulation of the mixed lymphocyte culture and generation of cytotoxic cells, Cell. Immunol. 56: 172.PubMedCrossRefGoogle Scholar
  14. Droller, M. J., Perlmann, P., and Schneider, M. U., 1978a, Enhancement of natural and antibody-dependent lymphocyte cytotoxicity by drugs which inhibit prostaglandin production by tumor target cells, Cell. Immunol. 39: 154.CrossRefGoogle Scholar
  15. Droller, M. J., Schneider, M. U., and Perlmann, P., 1978b, A possible role of prostaglandins in the inhibition of natural and antibody-dependent cell-mediated cytotoxicity against tumor cells, Cell. Immunol. 39: 165.CrossRefGoogle Scholar
  16. Eilber, F. R., Nizze, J. A., and Morton, D. L., 1975, Sequential evaluation of general immune competence in cancer patients: Correlation with clinical course, Cancer 35: 660.PubMedCrossRefGoogle Scholar
  17. Engleman, E. G., Hoppe, R., and Kaplan, H., 1978, Suppressor cells of the mixed lymphocyte reaction in healthy subjects and patients with Hodgkin’s disease and sarcoidosis, Clin. Res. 26: 513.Google Scholar
  18. Favalli, C., Garaci, E., Etheredge, E., Santoro, M. G., and Jaffe, B. M., 1980, Influence of PGE on the immune response in melanoma-bearing mice, J. Immunol. 125: 897.PubMedGoogle Scholar
  19. Fulton, A. M., and Levy, J. G., 1980, The possible role of prostaglandins in mediating immune suppression by nonspecific T suppressor cells, Cell. Immunol. 52: 29.PubMedCrossRefGoogle Scholar
  20. Gill, P. G., Waller, C. A., MacLennan, I. C. M., and Morris, P. J., 1980, Effect of intravenous Corynebacterium parvumon peripheral-blood effector cells of cancer patients, Br. J. Cancer 41: 782.PubMedCrossRefGoogle Scholar
  21. Golub, S. H., O’Connell, T. X., and Morton, D. L., 1974, Correlation of in vivoand in vitroassays of immunocompetence in cancer patients, Cancer Res. 34: 1833.PubMedGoogle Scholar
  22. Goodwin, J. S., and Messner, R. P., 1979, Sensitivity of lymphocytes to prostaglandin E2 increases in subjects over age 70, J. Clin. Invest. 64: 434.PubMedCrossRefGoogle Scholar
  23. Goodwin, J. S., and Webb, D. R., 1980, Regulation of the immune response by prostaglandins, Clin. Immunol. Immunopathol. 15: 106.PubMedCrossRefGoogle Scholar
  24. Goodwin, J. S., Bankhurst, A. D., and Messner, R. P., 1977a, Suppression of human T-cell mitogenesis by prostaglandin, J. Exp. Med. 146: 1719.CrossRefGoogle Scholar
  25. Goodwin, J. S., Messner, R. P., Bankhurst, A. D., Peake, G. T., Saiki, J. H., and Williams, R. C., Jr., 1977b, Prostaglandin-producing suppressor cells in Hodgkin’s disease, N. Engl. J. Med. 297: 963.CrossRefGoogle Scholar
  26. Goodwin, J. S., Messner, R. P., and Peake, G. T., 1978, Prostaglandin suppression of mitogen-stimulated lymphocytes: In vitrochanges with mitogen dose and preincubation, J. Clin. Invest. 62: 753.PubMedCrossRefGoogle Scholar
  27. Gordon, D., Bray, M., and Morley, J., 1976, Control of lymphokine secretion by prostaglandins, Nature (London) 262: 401.CrossRefGoogle Scholar
  28. Grimm, W., Seitz, M., Kirchner, H., and Gemsa, D., 1978, Prostaglandin synthesis in spleen cell cultures of mice injected with Corynebacterium parvum, Cell. Immunol. 40: 419.PubMedCrossRefGoogle Scholar
  29. Grinwich, K. D., and Plescia, O. J., 1977, Tumor-mediated immunosuppression: Prevention by inhibitors of prostaglandin synthesis, Prostaglandins 14: 1175.PubMedCrossRefGoogle Scholar
  30. Han, T., and Takita, H., 1980, Indomethacin-mediated enhancement of lymphocyte response to mitogens in healthy subjects and lung cancer patients, Cancer 46: 2416.PubMedCrossRefGoogle Scholar
  31. Henney, C. S., Boume, H.R., and Lichtenstein, L. M., 1972, The role of cyclic 3’,5’ adenosine monophosphate in the specific cytolytic activity of lymphocytes, J. Immunol. 108: 1526.PubMedGoogle Scholar
  32. Hersh, E. M., and Oppenheim, J. J., 1965, Impaired in vitrolymphocyte transformation in Hodgkin’s disease, N. Engl. J. Med. 273: 1006.PubMedCrossRefGoogle Scholar
  33. Hofer, D., Dubitsky, A., and Jaffe, B., 1980, Prostaglandin potentiation of the effect of chemotherapy on B-16 melanoma, Surg. Forum 31: 417.Google Scholar
  34. Humes, J. L., Bonney, R. J., Pelus, L. M., Dahlgren, M. E., Sadowski, F. A., Kuehl, F. A., Jr., and Davies, P., 1977, Macrophages synthesize and release prostaglandins in response to inflammatory stimuli, Nature (London) 269: 149.CrossRefGoogle Scholar
  35. Jaffe, B. M., Behrman, H. R., and Parker, C. W., 1973, Radioimmunoassay measurement of prostaglandin E, A, and F in human plasma, J. Clin. Invest. 52: 398.PubMedCrossRefGoogle Scholar
  36. Jerrells, T. R., Dean, J. H. Richardson, G. L., McCoy, J. L., and Herberman,R. B., 1978, Role of suppressor cells in depression of in vitrolymphoproliferative responses of lung and breast cancer patients, J. Natl. Cancer Inst. 61: 1001.PubMedGoogle Scholar
  37. Kantor, H. S., and Hampton, M., 1978, Indomethacin in submicromolar concentrations inhibit cyclic AMP-dependent protein kinase, Nature (London) 276: 841.CrossRefGoogle Scholar
  38. Karim, S. M. M., 1976, Prostaglandins and tumors, Adv. Prostaglandin Res. 2: 303.Google Scholar
  39. Kirchner, H., Glaser, M., and Herberman, R. B., 1975, Suppression of cell-mediated tumor immunity by Corynebacterium parvum, Nature (London) 257: 396.CrossRefGoogle Scholar
  40. Koopman, W. J., Gillis, M. H., and David J. R., 1973, Prevention of MIF activity by agents known to increase cellular cyclic AMP, J. Immunol. 110: 1609.PubMedGoogle Scholar
  41. Kurland, J. L., and Bockman, R., 1978, Prostaglandin E production by human monocytes and mouse macrophages, J. Exp. Med. 147: 95.CrossRefGoogle Scholar
  42. Lynch, N. R., and Salomon, S. C., 1979, Tumor growth inhibition and potentiation of immunotherapy by indomethacin in mice, J. Natl. Cancer Inst. 69: 97.Google Scholar
  43. Metzger, Z., Hoffeld, J. R., and Oppenheim, J. J., 1980, Macrophage mediated suppression. I. Evidence for participation of both hydrogen peroxide and prostaglandins in suppression of murine lymphocyte proliferation, J. Immunol. 124: 983.PubMedGoogle Scholar
  44. Murahata, R. I., and Zighelboim, J., 1979, Inhibition of cell-mediated cytotoxicity to tumor alloantigens by systemic administration of Corynebacterium parvum, Cancer Immunol. Immunother. 6: 101.CrossRefGoogle Scholar
  45. Ojo, E., Haller, O., Kimura, A., and Wigzell, H., 1978, An analysis of conditions allowing Corynebacterium parvumto cause either augmentation or inhibition of natural killer cell activity against tumor cells in mice, Int. J. Cancer 21: 444.PubMedCrossRefGoogle Scholar
  46. Pellegrino, M. A., Ferrone, S., Dierich, M. P., and Reisfeld, R. A., 1975, Enhancement of sheep red blood cell human lymphocyte rosette formation by the sulfhydryl compound 2-amino ethylisothiouronium bromide, Clin. Immunol. Immunopathol. 3: 324.PubMedCrossRefGoogle Scholar
  47. Pelus, L., and Bockman, R., 1979, Increased prostaglandin synthesis by macrophages from tumor-bearing mice. J. Immunol. 123: 2118.PubMedGoogle Scholar
  48. Pelus, L. M., and Strausser, H. R., 1976, Indomethacin enhancement of spleen-cell responsiveness to mitogen stimulation in tumorous mice, Int. J. Cancer 18: 653.PubMedCrossRefGoogle Scholar
  49. Picker, L. J., Raff, H. V., Goldyne, M. E., and Stobo, J. D., 1980, Metabolic heterogeneity among human monocytes and its modulation by PGE2, J. Immunol. 124: 2557.PubMedGoogle Scholar
  50. Plescia, O. J., Smith, A. H., and Grinwich, K., 1975, Subversion of immune system by tumor cells and role of prostaglandins, Proc. Natl. Acad. Sci. U.S.A. 72: 1848.PubMedCrossRefGoogle Scholar
  51. Santoro, M. G., Philpott, G. W., and Jaffe, B. M., 1976, Inhibition of tumor growth in vitroby prostaglandin E2, Nature (London) 263: 777.CrossRefGoogle Scholar
  52. Savary, C. A., and Lotzova, E., 1978, Suppression of natural killer cell cytotoxicity by splenocytes from Corynebacteriumparvum-injected, bone marrow-tolerant, and infant mice, J. Immunol. 120: 239.PubMedGoogle Scholar
  53. Schultz, R. M., Pavlidis, N. A., Stylos, W. A., and Chirigos, M. A., 1978, Regulation of macrophage tumoricidal function: A role for prostaglandins of the E series, Science 202: 320.Google Scholar
  54. Scott, M. T., 1972, Biological effects of the adjuvant Corynebacterium parvum. I. Inhibition of PHA, mixed lymphocyte and GVH reactivity, Cell. Immunol. 5: 459.PubMedCrossRefGoogle Scholar
  55. Shen, T. -Y., and Winter, C. A., 1977, Chemical and biological studies on indomethacin, sulindac and their analogs, Adv. Drug Res. 12: 89.Google Scholar
  56. Stenson, W. F., and Parker, C. W., 1980, Prostaglandins, macrophages, and immunity, J. Immunol. 125: 1.PubMedGoogle Scholar
  57. Stringfellow, D., and Fitzpatrick, F., 1979, Prostaglandin D2 controls pulmonary metastasis of malignant melanoma cells, Nature (London) 282: 76.CrossRefGoogle Scholar
  58. Thatcher, N., Swindell, R., and Crowther, D., 1979, Effect of Corynebacterium parvumand BCG therapy on immune parameters in patients with disseminated melanoma: A sequential study over 28 days. II. Changes in non-specific (NK, K and T cell) lymphocytoxicity and delayed hypersensitivity skin reactions, Clin. Immunol. 35: 171.Google Scholar
  59. Cracey, D. E., and Adkinson, N. F., Jr., 1980, Prostaglandin synthesis inhibitors potentiate the BCG-induced augmentation of natural killer cell activity, J. Immunol. 125: 136.Google Scholar
  60. Trevisani, A., Ferretti, E., Capuzzo, A., and Tomasi, V., 1980, Elevated levels of prostaglandin E2 in Yoshida hepatoma and the inhibition of tumour growth by non-steroidal anti-inflammatory drugs. Br. J. Cancer 41: 341.PubMedCrossRefGoogle Scholar
  61. Wanebo, H. J., Jun, M. Y., Strong. E. W., and Oettgen, H., 1975, T-cell deficiency in patients with squamous cell cancer of the head and neck, Am. J. Surg. 130: 445.Google Scholar
  62. Webb, D. R., and Osheroff, P. L., 1975, Antigen stimulation of prostaglandin synthesis and control of immune responses, Proc. Natl. Acad. Sci. U.S.A. 73: 1300.CrossRefGoogle Scholar
  63. Weiss, B., and Hait, W. N., 1977, Selective cyclic nucleotide phosphodisterase inhibitors as potential therapeutic agents, Annu. Rev. Pharmacol. Toxicol. 17: 441.CrossRefGoogle Scholar
  64. Yu, A., Watts, H., Jaffe, N., and Parkman, R., 1977, Concomitant presence of tumor-specific cytotoxic and inhibitor lymphocytes in patients with osteogenic sarcoma, N. Engl. J. Med. 297: 121.PubMedCrossRefGoogle Scholar
  65. Zembala, M., Mytar, B., Popiela, T., and Asherson, G. L., 1977, Depressed in vitroperipheral blood lym- phocyte response to mitogens in cancer patients: The role of suppressor cells, Int. J. Cancer 19: 605.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1982

Authors and Affiliations

  • Charles M. Balch
    • 1
  • Arabella B. Tilden
    • 1
  1. 1.Departments of Surgery and Microbiology; Cellular Immunobiology Unit, Comprehensive Cancer Center; Veterans HospitalUniversity of Alabama in BirminghamBirminghamUSA

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