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. 1994 Jan;39(1):53–58. doi: 10.1007/BF01517181

Increased expression of perforin and granzyme B genes in patients with metastatic melanoma treated with recombinant interleukin-2

Marie-Bénédicte Leger-Ravet 1, Claire Mathiot 2, Alain Portier 1, Maud Brandely 3, Pierre Galanaud 1, Wolf-Herman Fridman 4, Dominique Emilie 1,✉
PMCID: PMC11038965  PMID: 8044827

Abstract

The frequency of peripheral blood cells expressing the perforin gene or the granzyme B gene was evaluated by in situ hybridization in nine patients suffering from metastatic melanoma and treated with recombinant interleukin-2 (rIL-2). A spontaneous expression of both genes was detected in five to seven patients, rIL-2 administration increased the frequency of positive cells in all patients (P<0.03 for each gene), the highest frequency being reached in the patients who already expressed these genes prior to rIL-2 treatment (P<0.02). Expressions of the granzyme B gene and of the perforin gene were strongly correlated before IL-2 treatment and they were similarly affected by rIL-2 administration. In contrast, their modification under treatment did not correlate with that of CD56+ cell counts, of natural killer activity and of sCD8 release. This indicates that perforin and granzyme B gene expressions are markers of cytotoxic cell activation independent of those previously described, and that they should be further evaluated in patients with malignancies to delineate their potential value in predicting clinical outcome.

Key words: Melanoma, Interleukin-2, Cytotoxic T lymphocyte, Perforin, Granzyme B

References

  • 1.Barth RJ, Mulé JJ, Spiess PJ, Rosenberg SA. Inteferon γ and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes. J Exp Med. 1991;173:647. doi: 10.1084/jem.173.3.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Clément MV, Haddad P, Soulié A, Benvenuti C, Lichtenheld MG, Podack ER, Sigaux N, Sasportes M. Perforin and granzyme B as markers for acute rejection in heart transplantation. Int Immunol. 1991;3:1175. doi: 10.1093/intimm/3.11.1175. [DOI] [PubMed] [Google Scholar]
  • 3.Crowley NJ, Slingluff CL, Darrow TL, Siegler HF. Generation of human autologous melanoma specific cytotoxic T-cells using HLA-A2 matched allogenic melanomas. Cancer Res. 1990;50:492. [PubMed] [Google Scholar]
  • 4.Devergne O, Peuchmaur M, Crevon MC, Trapani JA, Maillot MC, Galanaud P, Emilie D. Activation of cytotoxic cells in hyperplastic lymph nodes from HIV-infected patients. AIDS. 1991;5:1071. doi: 10.1097/00002030-199109000-00002. [DOI] [PubMed] [Google Scholar]
  • 5.Golstein P, Ojcius DM, Young JDE. Cell mediated death mechanisms and the immune system. Immunol Rev. 1991;121:29. doi: 10.1111/j.1600-065x.1991.tb00822.x. [DOI] [PubMed] [Google Scholar]
  • 6.Griffiths GM, Mueller C. Expression of perforin and granzymes in vivo: potential diagnosis markers for activated cytotoxic cells. Immunol Today. 1991;12:415. doi: 10.1016/0167-5699(91)90145-J. [DOI] [PubMed] [Google Scholar]
  • 7.Hensel JW, Wesselschmidt RL, Ley TJ. Generation of mice deficient in the cytotoxic lymphocyte serine protease granzyme B (abstract 958) Blood. 1993;82(Suppl):243a. [Google Scholar]
  • 8.Hock H, Dorsch M, Kunzendorf U, Qin Z, Diamantstein T, Blankenstein T. Mechanisms of rejection induced by tumor cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or interferon γ. Proc Natl Acad Sci USA. 1993;90:2774. doi: 10.1073/pnas.90.7.2774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Humbert M, Devergne O, Cerrina J, Rain B, Simonneau G, Dartevelle P, Duroux P, Galanaud P, Emilie D. Activation of macrophages and cytotoxic cells during cytomegalovirus pneumonia complicating lung transplantations. Am Rev Respir Dis. 1992;145:1178. doi: 10.1164/ajrccm/145.5.1178. [DOI] [PubMed] [Google Scholar]
  • 10.Kast WM, Offringa R, Peters PJ, Voordouw AC, Meloen RH, van der Eb AJ, Melief CJM. Eradication of adenovirus El-induced tumors by EIA-specific cytotoxic T lymphocytes. Cell. 1989;59:603. doi: 10.1016/0092-8674(89)90006-8. [DOI] [PubMed] [Google Scholar]
  • 11.Kriegler M, Perez C, De Fay K, Albert I, Lu D. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell. 1988;53:45. doi: 10.1016/0092-8674(88)90486-2. [DOI] [PubMed] [Google Scholar]
  • 12.Léger-Ravet MB, Devergne O, Peuchmaur M, Solal-Celigny P, Brousse N, Gaulard P, Galanaud P, Emilie D. In situ detection of activated cytotoxic cells in follicular lymphomas. Am J Pathol. 1994;144:492. [PMC free article] [PubMed] [Google Scholar]
  • 13.Legha SS. Current therapy for melanoma. Semin Oncol. 1989;16:34. [PubMed] [Google Scholar]
  • 14.Lim SH, Worman C, Jewell A, Tsakona C, Giles FJ, Goldstone A. Lymphocyte activation and serine-esterase induction following recombinant interleukin-2 infusion for lymphomas and acute leukemias. Cancer Immunol Immunother. 1991;32:133. doi: 10.1007/BF01742542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Liu CC, Rafii S, Granelli-Piperno A, Trapani JA, Young JDE. Perforin and serine esterase gene expression in stimulated human T cells. Kinetics, mitogen requirements, and effects of cyclosporin A. J Exp Med. 1989;170:2105. doi: 10.1084/jem.170.6.2105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Manyak CL, Norton GP, Lobe CG, Bleackley RC, Gershengeld HK, Weissman IL, Kumar V, Sial NH, Koo GC. IL-2 induces expression of serine protease enzymes and genes in natural killer and non specific T killer cells. J Immunol. 1989;142:3707. [PubMed] [Google Scholar]
  • 17.Mc Clay EF, Mastrangelo MJ, Spandio JR. The importance of tamoxifen to a cisplatin-containing regimen in the treatment of metastatic melanoma. Cancer. 1989;63:1292. doi: 10.1002/1097-0142(19890401)63:7<1292::aid-cncr2820630711>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  • 18.Nishanian P, Hofmann B, Wang Y, Jackson AL, Detels R, Fahey JL. Serum soluble CD8 molecule is a marker of CD8 T-cell activation in HIV-1 disease. AIDS. 1991;5:805. doi: 10.1097/00002030-199107000-00003. [DOI] [PubMed] [Google Scholar]
  • 19.Parmiani G, Anichini A, Fossati G. Cellular immune response against autologous human malignant melanoma: are in vitro studies providing a frame work for a more effective immunotherapy. J Natl Cancer Inst. 1990;82:361. doi: 10.1093/jnci/82.5.361. [DOI] [PubMed] [Google Scholar]
  • 20.Peuchmaur M, Emilie D, Crevon MC, Solal-Celigny P, Maillot MC, Lemaigre G, Galanaud P. IL-2 mRNA expression of Tac-positive malignant lymphomas. Am J Pathol. 1990;136:383. [PMC free article] [PubMed] [Google Scholar]
  • 21.Peuchmaur M, Emilie D, Crevon MC, Brousse N, Gaulard P, Agay MF d', Galanaud P, Solal-Celigny P. Interleukin-2 and interferon-gamma production in follicular lymphomas. Am J Clin Pathol. 1991;95:55. doi: 10.1093/ajcp/95.1.55. [DOI] [PubMed] [Google Scholar]
  • 22.Ratner A, Clark WR. Role of TNF-α CD8+ cytotoxic T lymphocyte-mediated lysis. J Immunol. 1993;150:4303. [PubMed] [Google Scholar]
  • 23.Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan M, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE. A progress report on the treatment of 157 patients with advanced cancer using lymphokine activated killer cells and interleukin-2 or high dose interleukin-2 alone. N Engl J Med. 1987;316:889–897. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
  • 24.Smyth MJ, Ortaldo JR, Shinkai Y-I, Yagita H, Nakata M, Okomura K, Young HA. Interleukin 2 induction of pore-forming protein gene expression in human peripheral blood CD8+ T cells. J Exp Med. 1990;171:1269. doi: 10.1084/jem.171.4.1269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Tian Q, Streuli M, Saito H, Schlossman SF, Anderson P. A polyadenylate binding protein localized to the granules of cytotoxic lymphocytes induces DNA fragmentation in target cells. Cell. 1991;67:629. doi: 10.1016/0092-8674(91)90536-8. [DOI] [PubMed] [Google Scholar]
  • 26.Tolédano M, Mathiot C, Michon J, Andreu G, Lando D, Brandely M, Fridman WH. Interferon-γ (IFNγ) and interleukin-2 in the generation of lymphokine-activated killer cytotoxicity. IFNγ-induced suppressive activity. Cancer Immunol Immunother. 1989;30:57. doi: 10.1007/BF01665031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Tschopp J, Nabholz M. Perforin-mediated target cell lysis by cytolytic T lymphocytes. Annu Rev Immunol. 1990;8:279. doi: 10.1146/annurev.iy.08.040190.001431. [DOI] [PubMed] [Google Scholar]
  • 28.de Waal M, Verma S, Berajano MT, Ranes-Goldberg M, Hill M, Spits H. CD2/LFA-3 or LFA-1/ICAM-1 but not CD28/B7 interactions can augment cytotoxicity by virus-specific CD8+ cytotoxic T lymphocytes. Eur J Immunol. 1993;23:418. doi: 10.1002/eji.1830230218. [DOI] [PubMed] [Google Scholar]
  • 29.West WH, Tauer KW, Yanelli JR, Marshall GD, Orr DW, Thurman GB, Oldham RK. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med. 1987;316:898. doi: 10.1056/NEJM198704093161502. [DOI] [PubMed] [Google Scholar]
  • 30.Yander Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van Den Eynde B, Knuth A, Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1989;254:1643. doi: 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]

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