Cellular and Functional Characterization of Immunoresistant Human Glioma Cell Clones Selected With Alloreactive Cytotoxic T Lymphocytes Reveals Their Up-regulated Synthesis of Biologically Active TGF-β

Two immunoresistant (IR) glioma cell variants, 13-06-IR29 and 13-06-IR30, were cloned from 13-06-MG glioma cell populations after receiving continuous immunoselective pressure from multiple alloreactive cytotoxic T lymphocyte (aCTL) preparations. Reapplication of aCTL immunoselective pressure to the IR clones, displaying a partial regain in sensitivity to aCTL after removal of the selective pressure, restored the resistance. The IR variants exhibited cross-resistance to non-human leukocyte antigen (HLA)-restricted effector cells and γ-irradiation, but not to carmustine. The IR clones were characterized for factors that might contribute to the immunoresistance. The aCTL adhesion to extracellular matrix extracts derived from either the IR clones or the parental cells was similar and not impaired. Furthermore, aCTL binding to parental cells and IR clones was equal. Down-regulation of the cell recognition molecules, class I HLA or intercellular adhesion molecule-1 (ICAM-1), that would inhibit their recognition by aCTL was not observerd on the IR clones. The down-regulation of Fas by the IR clones correlated with their resistance to FasL-induced apoptosis. HLA-G or FasL that might provide an immunotolerant environment or provide a means of counterattack to aCTL, respectively, were not associated with the IR phenotype. The aCTL, coincubated with the IR clones and parental cells, displayed up-regulation of multiple secreted cytokines. A significant up-regulation of bioactive transforming growth factor (TGF)-β was observed in the IR clones compared with the parental cells. These data suggest that increased secretion of bioactive TGF-β may inhibit aCTL lysis of the IR clones. Disruption of the TGF-β signaling pathway may circumvent the resistance.

[1]  T. Witham,et al.  Expression of a soluble transforming growth factor-β (TGFβ) receptor reduces tumorigenicity by regulating natural killer (NK) cell activity against 9L gliosarcomain vivo , 2003, Journal of Neuro-Oncology.

[2]  W. Franklin,et al.  Characterization of a continuous human glioma cell line DBTRG-05MG: growth kinetics, karyotype, receptor expression, and tumor suppressor gene analyses , 1992, In Vitro Cellular & Developmental Biology - Animal.

[3]  M. Varella‐Garcia,et al.  Isolation of immunoresistant human glioma cell clones after selection with alloreactive cytotoxic T lymphocytes: cytogenetic and molecular cytogenetic characterization. , 2006, Cancer genetics and cytogenetics.

[4]  C. Kruse,et al.  Subsets within alloreactive CTL (aCTL) exhibit upregulated proinflammatory cytokine secretion: aCTL response to coincubation with irrelevant and relevant parental and immunoresistant (IR) gliomas , 2006 .

[5]  N. Bercovici,et al.  Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate , 2006, Cancer Immunology, Immunotherapy.

[6]  J. Massagué,et al.  TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. , 2005, Cancer cell.

[7]  Jack T. Lin,et al.  TGF-β1 Uses Distinct Mechanisms to Inhibit IFN-γ Expression in CD4+ T Cells at Priming and at Recall: Differential Involvement of Stat4 and T-bet1 , 2005, The Journal of Immunology.

[8]  Erwin G. Van Meir,et al.  The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. , 2005, Neuro-oncology.

[9]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[10]  S. Ferrone,et al.  Immune Selection of Hot-Spot β2-Microglobulin Gene Mutations, HLA-A2 Allospecificity Loss, and Antigen-Processing Machinery Component Down-Regulation in Melanoma Cells Derived from Recurrent Metastases following Immunotherapy1 , 2005, The Journal of Immunology.

[11]  Jack T. Lin,et al.  TGF-beta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet. , 2005, Journal of immunology.

[12]  B. Eliceiri,et al.  Glioma cell integrin expression and their interactions with integrin antagonists: Research Article. , 2005, Cancer therapy.

[13]  I. Egorov Mouse models of efficient and inefficient anti-tumor immunity, with emphasis on minimal residual disease and tumor escape , 2005, Cancer Immunology, Immunotherapy.

[14]  R. McCarron,et al.  Mechanisms by which human gliomas may escape cellular immune attack , 2005, Acta Neurochirurgica.

[15]  M. Weller,et al.  RNA Interference Targeting Transforming Growth Factor-β Enhances NKG2D-Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates Tumorigenicity In vivo , 2004, Cancer Research.

[16]  J. Modiano,et al.  Fas ligand-dependent suppression of autoimmunity via recruitment and subsequent termination of activated T cells. , 2004, Clinical immunology.

[17]  L. Gerschenson,et al.  Interactions of the allogeneic effector leukemic T cell line, TALL-104, with human malignant brain tumors. , 2004, Neuro-oncology.

[18]  T. Witham,et al.  Expression of a Soluble Transforming Growth Factor-β (TGFβ) receptor reduces tumorigenicity by regulating natural killer (NK) cell activity against 9L gliosarcoma in vivo , 2004, Journal of Neuro-Oncology.

[19]  Chulhee Choi,et al.  Fas Engagement Increases Expression of Interleukin-6 in Human Glioma Cells , 2004, Journal of Neuro-Oncology.

[20]  Barry H. Smith,et al.  Ultrastructural features of the lymphocyte-stimulated halos produced by human glioma-derived cells in vitro , 2004, Journal of Neuro-Oncology.

[21]  C. Chao,et al.  Up-regulation of FLIP in cisplatin-selected HeLa cells causes cross-resistance to CD95/Fas death signalling. , 2003, The Biochemical journal.

[22]  F. Faure,et al.  Exosomes bearing HLA-G are released by melanoma cells. , 2003, Human immunology.

[23]  Steven A. Rosenberg,et al.  Cell Transfer Therapy for Cancer: Lessons from Sequential Treatments of a Patient With Metastatic Melanoma , 2003, Journal of immunotherapy.

[24]  D. B. Paul,et al.  Human Alloreactive CTL Interactions with Gliomas and with Those Having Upregulated HLA Expression from Exogenous IFN-γ or IFN-γ Gene Modification , 2003 .

[25]  A. Belldegrun,et al.  Immunosensitization of resistant human tumor cells to cytotoxicity by tumor infiltrating lymphocytes. , 2003, International journal of oncology.

[26]  D. B. Paul,et al.  Human alloreactive CTL interactions with gliomas and with those having upregulated HLA expression from exogenous IFN-gamma or IFN-gamma gene modification. , 2003, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[27]  Pedro Romero,et al.  Matrix metalloproteinase 9 (MMP-9/gelatinase B) proteolytically cleaves ICAM-1 and participates in tumor cell resistance to natural killer cell-mediated cytotoxicity , 2002, Oncogene.

[28]  M. Simon,et al.  Antigen-Dependent Release of IFN-γ by Cytotoxic T Cells Up-Regulates Fas on Target Cells and Facilitates Exocytosis-Independent Specific Target Cell Lysis , 2002, The Journal of Immunology.

[29]  M. Weller,et al.  A Functional Role of HLA-G Expression in Human Gliomas: An Alternative Strategy of Immune Escape1 , 2002, The Journal of Immunology.

[30]  F. Garrido,et al.  Impaired surface antigen presentation in tumors: implications for T cell-based immunotherapy. , 2002, Seminars in cancer biology.

[31]  C. Kruse,et al.  Effects of IFN-gamma and interleukin-1beta on major histocompatibility complex antigen and intercellular adhesion molecule-1 expression by 9L gliosarcoma: relevance to its cytolysis by alloreactive cytotoxic T lymphocytes. , 2002, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[32]  Chun-Ming Lin,et al.  Activated human CD4+ T cells induced by dendritic cell stimulation are most sensitive to transforming growth factor-beta: implications for dendritic cell immunization against cancer. , 2002, Clinical immunology.

[33]  C. Kruse,et al.  Strategies using the immune system for therapy of brain tumors. , 2001, Hematology/oncology clinics of North America.

[34]  K. Kiura,et al.  Generation of cytotoxic T lymphocytes against autologous lung cancer cells resistant to apoptosis. , 2001, Anticancer research.

[35]  K. Kiura,et al.  Tumor-specific cytotoxic T lymphocyte responses against chondrosarcoma with HLA haplotype loss restricted by the remaining HLA class I allele. , 2001, Biochemical and biophysical research communications.

[36]  X. Xu,et al.  Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. , 2001, Cancer research.

[37]  B. Weinshenker,et al.  Genetic variation in the transforming growth factor β1 gene in multiple sclerosis , 2001, Journal of Neuroimmunology.

[38]  R. Merchant,et al.  IL-6 Secretion by a Rat T9 Glioma Clone Induces a Neutrophil-Dependent Antitumor Response with Resultant Cellular, Antiglioma Immunity1 , 2001, The Journal of Immunology.

[39]  Carol A. Kruse,et al.  Cytotoxic T-Lymphocytes Reactive to Patient Major Histocompatibility Complex Proteins for Therapy of Brain Tumors , 2001 .

[40]  R. Flavell,et al.  Cutting Edge: TGF-β Inhibits Th Type 2 Development Through Inhibition of GATA-3 Expression , 2000, The Journal of Immunology.

[41]  D. B. Paul,et al.  The human leukemic T-cell line, TALL-104, is cytotoxic to human malignant brain tumors and traffics through brain tissue: implications for local adoptive immunotherapy. , 2000, Cancer research.

[42]  M. Simon,et al.  Cytotoxic T Cells Specifically Induce Fas on Target Cells, Thereby Facilitating Exocytosis-Independent Induction of Apoptosis1 , 2000, The Journal of Immunology.

[43]  S. Rhodes,et al.  Identification of transforming growth factor‐β1‐binding protein overexpression in carmustine‐resistant glioma cells by MRNA differential display , 2000 .

[44]  L. Salford,et al.  Expression of TGF‐β isoforms, TGF‐β receptors, and SMAD molecules at different stages of human glioma , 2000 .

[45]  D. Hunt,et al.  Melanomas with concordant loss of multiple melanocytic differentiation proteins: immune escape that may be overcome by targeting unique or undefined antigens , 2000, Cancer Immunology, Immunotherapy.

[46]  R. Flavell,et al.  Abrogation of TGFβ Signaling in T Cells Leads to Spontaneous T Cell Differentiation and Autoimmune Disease , 2000 .

[47]  R. Flavell,et al.  Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. , 2000, Immunity.

[48]  L. Salford,et al.  Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma. , 2000, International journal of cancer.

[49]  T. Roszman,et al.  Immune defects observed in patients with primary malignant brain tumors , 1999, Journal of Neuroimmunology.

[50]  R. Offringa,et al.  Immune Escape of Tumors in Vivo by Expression of Cellular Flice-Inhibitory Protein , 1999, The Journal of experimental medicine.

[51]  J. Dausset,et al.  HLA-G inhibits the allogeneic proliferative response. , 1999, Journal of reproductive immunology.

[52]  A. Régnault,et al.  TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. , 1999, Journal of immunology.

[53]  H. Rammensee,et al.  TGF‐β‐independent induction of immunogenicity by decorin gene transfer in human malignant glioma cells , 1999 .

[54]  H. Rammensee,et al.  TGF-beta-independent induction of immunogenicity by decorin gene transfer in human malignant glioma cells. , 1999, European Journal of Immunology.

[55]  J. Laterra,et al.  IL-10 gene transfer to intracranial 9L glioma: tumor inhibition and cooperation with IL-2 , 1998, Journal of Neuroimmunology.

[56]  Charles B. Wilson,et al.  Primary central nervous system tumors: Advances in knowledge and treatment , 1998, CA: a cancer journal for clinicians.

[57]  J. Westwick,et al.  Chemokines: understanding their role in T-lymphocyte biology. , 1998, The Biochemical journal.

[58]  T. Ohnishi,et al.  In vitro and in vivo potentiation of radiosensitivity of malignant gliomas by antisense inhibition of the RAD51 gene. , 1998, Biochemical and biophysical research communications.

[59]  J. Stears,et al.  Treatment of recurrent glioma with intracavitary alloreactive cytotoxic T lymphocytes and interleukin-2 , 1997, Cancer Immunology, Immunotherapy.

[60]  C. Kruse,et al.  Artificial‐capillary‐systemdevelopment of human alloreactive cytotoxic T‐lymphocytes that lyse brain tumour , 1997 .

[61]  P. Walker,et al.  Role of Fas ligand (CD95L) in immune escape: the tumor cell strikes back. , 1997, Journal of immunology.

[62]  C. Kruse,et al.  Artificial-capillary-system development of human alloreactive cytotoxic T-lymphocytes that lyse brain tumours. , 1997, Biotechnology and applied biochemistry.

[63]  S. Coons,et al.  Dichotomy of astrocytoma migration and proliferation , 1996, International journal of cancer.

[64]  D. Mercola,et al.  Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[65]  F. Marincola,et al.  Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. , 1996, Journal of the National Cancer Institute.

[66]  B. Drénou,et al.  The HLA-G gene is expressed at a low mRNA level in different human cells and tissues. , 1994, Human immunology.

[67]  F. Marincola,et al.  Loss of HLA haplotype and B locus down-regulation in melanoma cell lines. , 1994, Journal of immunology.

[68]  K. Stefansson,et al.  Inhibition of T cell activation by the extracellular matrix protein tenascin. , 1994, Journal of immunology.

[69]  T. Libermann,et al.  Coexpression of Interleukin-1β and Interleukin-6 in Human Brain Tumors , 1994 .

[70]  T. Libermann,et al.  Coexpression of interleukin-1 beta and interleukin-6 in human brain tumors. , 1994, Neurosurgery.

[71]  L. Clement,et al.  Heterogeneous mechanisms of human cytotoxic T lymphocyte generation. II. Differential effects of IL-6 on the helper cell-independent generation of CTL from CD8+ precursor subpopulations. , 1993, Journal of immunology.

[72]  A. Gritzapis,et al.  Elevated prostaglandin E2 production by monocytes is responsible for the depressed levels of natural killer and lymphokine‐activated killer cell function in patients with breast cancer , 1993, Cancer.

[73]  U. Bogdahn,et al.  The effect of transforming growth factor-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. , 1993, Journal of neurosurgery.

[74]  J. Murray,et al.  Linkage localization of TGFB2 and the human homeobox gene HLX1 to chromosome 1q. , 1993, Genomics.

[75]  Erwin G. Van Meir,et al.  Interleukin-8 is produced in neoplastic and infectious diseases of the human central nervous system. , 1992, Cancer research.

[76]  D. Constam,et al.  Differential expression of transforming growth factor-beta 1, -beta 2, and -beta 3 by glioblastoma cells, astrocytes, and microglia. , 1992, Journal of immunology.

[77]  H. Young,et al.  Regulation of lymphokine-activated killer activity and pore-forming protein gene expression in human peripheral blood CD8+ T lymphocytes. Inhibition by transforming growth factor-beta. , 1991, Journal of immunology.

[78]  P. Nowell,et al.  Growth factor requirements of childhood acute T-lymphoblastic leukemia: correlation between presence of chromosomal abnormalities and ability to grow permanently in vitro. , 1991, Blood.

[79]  Erwin G. Van Meir,et al.  Human glioblastoma cells release interleukin 6 in vivo and in vitro. , 1990, Cancer research.

[80]  S. Rosenberg,et al.  Immunoselection of a human melanoma resistant to specific lysis by autologous tumor-infiltrating lymphocytes. Possible mechanisms for immunotherapeutic failures. , 1990, Journal of immunology.

[81]  K. Frei,et al.  Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2. , 1989, Journal of immunology.

[82]  G. Moore,et al.  Interleukin‐2—activated lymphocytes from brain tumor patients. A comparison of two preparations generated in vitro , 1989, Cancer.

[83]  R. Supino,et al.  Generation and partial characterization of melanoma sublines resistant to lymphokine activated killer (LAK) cells. Relevance to doxorubicin resistance , 1989, International journal of cancer.

[84]  T. Espevik,et al.  Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha , 1987, The Journal of experimental medicine.

[85]  L. Muul,et al.  In vitro studies on the cell-mediated immune response to human brain tumors. II. Leukocyte-induced coats of glycosaminoglycan increase the resistance of glioma cells to cellular immune attack. , 1984, Journal of immunology.

[86]  M. Gately,et al.  Lymphoid cell-glioma cell interaction enhances cell coat production by human gliomas: novel suppressor mechanism. , 1983, Science.

[87]  P. Medawar Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. , 1948, British journal of experimental pathology.