Abstract
Adherent lymphokine-activated killer (A-LAK) cells were obtained from peripheral blood lymphocytes of patients with recurrent glioblastoma. In vitro features of A-LAK cultures were assessed in comparison to those of non-adherent lymphokine-activated killer (NA-LAK) cells of the same patients with regard to cytotoxic activity, proliferation and surface markers. Only in a minority of cases did A-LAK cells show a markedly higher cytotoxicity on K562, Daudi and allogeneic glioblastoma cells. Nevertheless, A-LAK cells proliferated significantly better than NA-LAK and contained higher percentages of CD16+, CD56+ and CD25+ cells, indicating that A-LAK cells from these patients represent a subpopulation of lymphocytes enriched for activated natural killer cells. We also investigated whether immunosuppressive factor(s) were present in the tumour bed of recurrent gliomas. To this end, samples of glioblastoma cavity fluid (GCF), which accumulates in the cavity of subtotally removed tumour, were recovered and tested for the presence of immunosuppressive activity. All GCF samples analysed were shown to inhibit in vitro proliferation and antitumour cytotoxicity of 1-week-cultured A-LAK cells in a dose-dependent manner. Such GCF activity was effectively antagonized by a transforming growth factor β (TGFβ) neutralizing antibody, indicating the involvement of TGFβ in lymphocyte inhibition. These results show that in the tumour cavity remaining after subtotal glioblastoma resection a marked immunosuppressive activity, probably due to local release of TGFβ, is present; such activity may negatively influence the therapeutic effectiveness of local cellular immunotherapy.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Bodmer S, Strommer K, Frei K, Siepl C, de Tribolet N, Heid I, Fontana A (1989) Immunosuppression and transforming growth factor-β in glioblastoma. Preferential production of transforming growth factor-β2. J Immunol 143: 3222
Brooks WH, Netsky MG, Normansell DE, Horwitz DA (1972) Depressed cell-mediated immunity in patients with primary intracranial tumors. J Exp Med 136: 1631
De Martin R, Haendler B, Hofer-Warbinek R, Gaugitsch H, Wrann M, Schlusener H, Seifert JM, Bodmer S, Fontana A, Hofer E (1987) Complementary DNA for human glioblastoma-derived T cell suppressor factor, a novel member of the transforming growth factor-β gene family. EMBO J 6: 3673
Elliott LH, Brooks WH, Roszman TL (1992) Suppression of high affinity IL-2 receptors on mitogen activated lymphocytes by gliomaderived suppressor factor. J Neurooncol 14: 1
Espevik T, Figari IS, Ranges GE, Palladino MA Jr (1988) Transforming growth factor-β1 (TGF-β1) and recombinant human tumor necrosis factor-α reciprocally regulate the generation of lymphokineactivated killer cell activity. Comparison between natural porcine platelet-derived TGF-β1 and TGF-β2, and recombinant human TGF-β1. J Immunol 140: 2312
Fontana A, Hengartner H, de Tribolet N, Weber E (1984) Glioblastoma cells release interleukin-1 and factors inhibiting interleukin-2 mediated effects. J Immunol 132: 1837
Fontana A, Frei K, Bodmer S, Hofer E, Schreier MH, Palladino MA Jr, Zinkernagel RM (1989) Transforming growth factor-β inhibits the generation of cytotoxic T cells in virus-infected mice. J Immunol 143: 323
Inge TH, Hoover SK, Susskind BM, Barrett SK, Bear HD (1992) Inhibition of tumor-specific cytotoxic T-lymphocyte responses by transforming growth factor-β1. Cancer Res 52: 1386
Ioli G, Yamamoto R, Jacques D, Neal J, Granger G (1992) Blocking factors (soluble receptors) for human TNF and LT in the serum, cerebrospinal fluid (CSF) and tumor cyst fluid (TCF) of human glioma patients. Proc Am Assoc Cancer Res 33: 309
Jaaskelainen J, Kalliomaki P, Paetau A, Timonen T (1989) Effect of LAK cells against three-dimensional tumor tissue. In vitro study using multi-cellular human glioma spheroids as targets. J Immunol 142: 1036
Jaaskelainen J, Maenpaa A, Patarroyo M, Gahmberg CG, Somersalo K, Tarkkanen J, Kallio M, Timonen T (1992) Migration of recombinant IL-2-activated T and natural killer cells in the intercellular space of human H-2 glioma spheroids in vitro. A study on adhesion molecules involved. J Immunol 149: 260
Jaeckle KA, Mittelman A, Hill FH (1990) Phase II trial ofSerratia marcescens extract in recurrent malignant astrocytoma. J Clin Oncol 8: 1408
Kehrl JH, Wakefield LM, Roberts AB, Jakowlew S, Alvarez-Mon M, Derynck R, Sporn MB, Fauci AS (1986) Production of transforming growth factor-β by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 163: 1037
Kuppner MC, Hamou MF, Bodmer S, Fontana A, de Tribolet N (1988) The glioblastoma-derived T-cell suppressor factor/transforming growth factor-β2 inhibits the generation of lymphokine-activated killer (LAK) cells. Int J Cancer 42: 562
Kuppner MC, Hamou MF, Sawamura Y, Bodmer S, de Tribolet N (1989) Inhibition of lymphocyte function by glioblastoma-derived transforming growth factor-β2. J Neurosurg 71: 211
Kuppner MC, Sawamura Y, Hamou MF, de Tribolet N (1990) Influence of PGE2 and cAMP-modulating agents on human glioblastoma cell killing by interleukin-2 activated lymphocytes. J Neurosurg 72: 619
Mahaley MS, Brooks WH, Roszman TL, Bigner DD, Dudka L, Richardson S (1977) Immunobiology of primary intracranial tumors. Part I. Studies of the cellular and humoral general immune competence of brain tumor patients. J Neurosurg 46: 467
Melder RJ, Whiteside TL, Vujanovic NL, Hiserodt JC, Herberman RB (1988) A new approach to generating antitumor effectors for adoptive immunotherapy using adherent lymphokine-activated killer cells. Cancer Res 48: 3461
Merchant RE, Ellison MD, Young HF (1990) Immunotherapy for malignant glioma using human recombinant interleukin-2 and activated autologous lymphocytes. A review of preclinical and clinical investigations. J Neurooncol 8: 173
Mulé JJ, Schwarz SL, Roberts AB, Sporn MB, Rosenberg SA (1988) Transforming growth factor-β inhibits the in vitro generation of lymphokine-activated killer cells and cytotoxic T cells. Cancer Immunol Immunother 26: 95
Nitta T, Sato K, Yagita H, Okumura K, Ishii S (1990) Preliminary trial of specific targeting therapy against malignant glioma. Lancet 335: 368
Palma L, Di Lorenzo N, Guidetti B (1978) Lymphocyte infiltrates in primary glioblastomas and recidivous gliomas. Incidence, fate and relevance to prognosis in 228 operated cases. J Neurosurg 49: 854
Ranges GE, Figari IS, Espevik T, Palladino MA Jr (1987) Inhibition of cytotoxic T cell development by transforming growth factor-β and reversal by recombinant tumor necrosis factor α. J Exp Med 166: 991
Rivoltini L, Cattoretti G, Arienti F, Mastroianni A, Melani C, Colombo MP, Parmiani G (1991) The high lysability by LAK cells of colon-carcinoma cells resistant to doxorubicin is associated with a high expression of ICAM-1, LFA-3, NCA and a less-differentiated phenotype. Int J Cancer 47: 746
Rivoltini L, Arienti F, Orazi A, Cefalo G, Gasparini M, Gambacorti-Passerini C, Fossati-Bellani F, Parmiani G (1992) Phenotypic and functional analysis of lymphocytes infiltrating paediatric tumors, with a characterization of the tumor phenotype. Cancer Immunol Immunother 34: 241
Rook AH, Kehrl JH, Wakefield LM, Roberts AB, Sporn MB, Burlington DB, Lane HC, Fauci AS (1986) Effects of transforming growth factor-β on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol 136: 3916
Roszman T, Elliott L, Brooks W (1991) Modulation of T-cell function by gliomas. Immunol Today 12: 370
Sander B, Andersson J, Andersson U (1991) Assessment of cytokines by immunofluorescence and the paraformaldehyde-saponin procedure. Immunol Rev 119: 65
Sawamura Y, Diserens AC, de Tribolet N (1990) In vitro prostaglandin E2 production by glioblastoma cells and its effect on interleukin-2 activation of oncolytic lymphocytes. J Neurooncol 9: 125
Schuster JM, Bigner DD (1992) Immunotherapy and monoclonal antibody therapies. Curr Opin Oncol 4: 547
Schwarz RE, Vujanovic NL, Hiserodt JC (1989) Enhanced antimetastatic activity of lymphokine-activated killer cells purified and expanded by their adherence to plastic. Cancer Res 49: 1441
Schwyzer M, Fontana A (1985) Partial purification and biochemical characterization of a T cell suppressor factor produced by human glioblastoma cells. J Immunol 134: 1003
Siepl C, Bodmer S, Frei K, Robson MacDonald H, De Martin R, Hofer E, Fontana A (1988) The glioblastoma-derived T cell suppressor factor/transforming growth factor-β2 inhibits T cell growth without affecting the interaction of interleukin-2 with its receptor. Eur J Immunol 18: 593
Smyth MJ, Strobl SL, Young HA, Ortaldo JR, Ochoa AC (1991) Regulation of lymphokine-activated killer activity and pore-forming protein gene expression in human peripheral blood CD8+ T lymphocytes. Inhibition by transforming growth factor-β. J Immunol 146: 3289
Torre-Amione G, Beauchamp RD, Koeppen H, Park BH, Schreiber H, Moses HL, Rowley DA (1990) A highly immunogenic tumor transfected with a murine transforming growth factor type β1 cDNA escapes immune surveillance. Proc Natl Acad Sci USA 87: 1486
Ushio Y (1991) Treatment of gliomas in adults. Curr Opin Oncol 3: 467
Whiteside TL, Wang YL, Selker RG, Herberman RB (1988) In vitro generation and antitumor activity of adherent lymphokine-activated killer cells from the blood of patients with brain tumors. Cancer Res 48: 6069
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ruffini, P.A., Rivoltini, L., Silvani, A. et al. Factors, including transforming growth factor β, released in the glioblastoma residual cavity, impair activity of adherent lymphokine-activated killer cells. Cancer Immunol Immunother 36, 409–416 (1993). https://doi.org/10.1007/BF01742258
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01742258