Induction and maintenance of T-cell response to a nonimmunogenic murine mesothelioma cell line requires expression of B7-1 and the capacity to upregulate class II major histocompatibility complex expression

Clement Leong, Julia Marley, S. Loh, Bruce Robinson, Michael Garlepp

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    Abstract

    Intratumoral expression of the T-cell costimulator B7-1 has been reported to induce tumor-specific immunity against immunogenic, but not nonimmunogenic, tumors. We transfected the B7-1 gene into a nonimmunogenic murine mesothelioma cell line that constitutively expresses high levels of class I major histocompatibility complex (MHC) and transforming growth factor-beta (TGF-beta). Tumor development by two of the four B7-1 transfectant clones was markedly delayed, although all clones eventually formed tumors. Retardation of tumor growth required both CD4(+) and CD8(+) T cells. Tumor-specific cytotoxic T-lymphocytes (CTLs) were elicited in response to the least (AC29-B7-6), but not the most (AC29-B7-7), tumorigenic transfectant clone. Tumor-specific CTL activity could be detected at early time points but not at the time of tumor outgrowth. This lack of responsiveness was tumor antigen specific. Differences in immunogenicity of transfectant clones did not relate to the level of expression of MHC class I, vascular cell adhesion molecule-1, or transfected B7-1, or to the level of TGF-beta secreted. Class II MHC expression was most readily inducible in those transfectant clones whose growth in vivo was most delayed. An explant cell line derived from a tumor that developed from AC29-B7-6 had a markedly reduced capacity to upregulate MHC class II expression and produced tumors in vivo at a faster rate than did the parental cell line. Thus, B7-1 expression in this nonimmunogenic tumor cell line can promote the generation of tumor-specific CTLs with consequent retardation of tumor development, and coexpression of MHC class II seems likely to play an important role in this process. This work also illustrates that clonal heterogeneity within a single tumor and the development of immunological nonresponsiveness resulting in tumor outgrowth, even in the presence of continued B7-1 expression, are potential difficulties associated with this therapeutic approach.
    Original languageEnglish
    Pages (from-to)321-330
    JournalCancer Gene Therapy
    Volume3
    Issue number5
    Publication statusPublished - Sep 1996

    Fingerprint

    Mesothelioma
    Major Histocompatibility Complex
    Up-Regulation
    Maintenance
    T-Lymphocytes
    Cell Line
    Neoplasms
    Clone Cells
    Cytotoxic T-Lymphocytes
    Transforming Growth Factor beta
    Vascular Cell Adhesion Molecule-1
    Neoplasm Antigens
    Growth
    Tumor Cell Line
    Immunity

    Cite this

    @article{d4269c1879be438797d8ded50c075d1a,
    title = "Induction and maintenance of T-cell response to a nonimmunogenic murine mesothelioma cell line requires expression of B7-1 and the capacity to upregulate class II major histocompatibility complex expression",
    abstract = "Intratumoral expression of the T-cell costimulator B7-1 has been reported to induce tumor-specific immunity against immunogenic, but not nonimmunogenic, tumors. We transfected the B7-1 gene into a nonimmunogenic murine mesothelioma cell line that constitutively expresses high levels of class I major histocompatibility complex (MHC) and transforming growth factor-beta (TGF-beta). Tumor development by two of the four B7-1 transfectant clones was markedly delayed, although all clones eventually formed tumors. Retardation of tumor growth required both CD4(+) and CD8(+) T cells. Tumor-specific cytotoxic T-lymphocytes (CTLs) were elicited in response to the least (AC29-B7-6), but not the most (AC29-B7-7), tumorigenic transfectant clone. Tumor-specific CTL activity could be detected at early time points but not at the time of tumor outgrowth. This lack of responsiveness was tumor antigen specific. Differences in immunogenicity of transfectant clones did not relate to the level of expression of MHC class I, vascular cell adhesion molecule-1, or transfected B7-1, or to the level of TGF-beta secreted. Class II MHC expression was most readily inducible in those transfectant clones whose growth in vivo was most delayed. An explant cell line derived from a tumor that developed from AC29-B7-6 had a markedly reduced capacity to upregulate MHC class II expression and produced tumors in vivo at a faster rate than did the parental cell line. Thus, B7-1 expression in this nonimmunogenic tumor cell line can promote the generation of tumor-specific CTLs with consequent retardation of tumor development, and coexpression of MHC class II seems likely to play an important role in this process. This work also illustrates that clonal heterogeneity within a single tumor and the development of immunological nonresponsiveness resulting in tumor outgrowth, even in the presence of continued B7-1 expression, are potential difficulties associated with this therapeutic approach.",
    author = "Clement Leong and Julia Marley and S. Loh and Bruce Robinson and Michael Garlepp",
    year = "1996",
    month = "9",
    language = "English",
    volume = "3",
    pages = "321--330",
    journal = "Cancer Gene Therapy",
    issn = "0929-1903",
    publisher = "Nature Publishing Group",
    number = "5",

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    TY - JOUR

    T1 - Induction and maintenance of T-cell response to a nonimmunogenic murine mesothelioma cell line requires expression of B7-1 and the capacity to upregulate class II major histocompatibility complex expression

    AU - Leong, Clement

    AU - Marley, Julia

    AU - Loh, S.

    AU - Robinson, Bruce

    AU - Garlepp, Michael

    PY - 1996/9

    Y1 - 1996/9

    N2 - Intratumoral expression of the T-cell costimulator B7-1 has been reported to induce tumor-specific immunity against immunogenic, but not nonimmunogenic, tumors. We transfected the B7-1 gene into a nonimmunogenic murine mesothelioma cell line that constitutively expresses high levels of class I major histocompatibility complex (MHC) and transforming growth factor-beta (TGF-beta). Tumor development by two of the four B7-1 transfectant clones was markedly delayed, although all clones eventually formed tumors. Retardation of tumor growth required both CD4(+) and CD8(+) T cells. Tumor-specific cytotoxic T-lymphocytes (CTLs) were elicited in response to the least (AC29-B7-6), but not the most (AC29-B7-7), tumorigenic transfectant clone. Tumor-specific CTL activity could be detected at early time points but not at the time of tumor outgrowth. This lack of responsiveness was tumor antigen specific. Differences in immunogenicity of transfectant clones did not relate to the level of expression of MHC class I, vascular cell adhesion molecule-1, or transfected B7-1, or to the level of TGF-beta secreted. Class II MHC expression was most readily inducible in those transfectant clones whose growth in vivo was most delayed. An explant cell line derived from a tumor that developed from AC29-B7-6 had a markedly reduced capacity to upregulate MHC class II expression and produced tumors in vivo at a faster rate than did the parental cell line. Thus, B7-1 expression in this nonimmunogenic tumor cell line can promote the generation of tumor-specific CTLs with consequent retardation of tumor development, and coexpression of MHC class II seems likely to play an important role in this process. This work also illustrates that clonal heterogeneity within a single tumor and the development of immunological nonresponsiveness resulting in tumor outgrowth, even in the presence of continued B7-1 expression, are potential difficulties associated with this therapeutic approach.

    AB - Intratumoral expression of the T-cell costimulator B7-1 has been reported to induce tumor-specific immunity against immunogenic, but not nonimmunogenic, tumors. We transfected the B7-1 gene into a nonimmunogenic murine mesothelioma cell line that constitutively expresses high levels of class I major histocompatibility complex (MHC) and transforming growth factor-beta (TGF-beta). Tumor development by two of the four B7-1 transfectant clones was markedly delayed, although all clones eventually formed tumors. Retardation of tumor growth required both CD4(+) and CD8(+) T cells. Tumor-specific cytotoxic T-lymphocytes (CTLs) were elicited in response to the least (AC29-B7-6), but not the most (AC29-B7-7), tumorigenic transfectant clone. Tumor-specific CTL activity could be detected at early time points but not at the time of tumor outgrowth. This lack of responsiveness was tumor antigen specific. Differences in immunogenicity of transfectant clones did not relate to the level of expression of MHC class I, vascular cell adhesion molecule-1, or transfected B7-1, or to the level of TGF-beta secreted. Class II MHC expression was most readily inducible in those transfectant clones whose growth in vivo was most delayed. An explant cell line derived from a tumor that developed from AC29-B7-6 had a markedly reduced capacity to upregulate MHC class II expression and produced tumors in vivo at a faster rate than did the parental cell line. Thus, B7-1 expression in this nonimmunogenic tumor cell line can promote the generation of tumor-specific CTLs with consequent retardation of tumor development, and coexpression of MHC class II seems likely to play an important role in this process. This work also illustrates that clonal heterogeneity within a single tumor and the development of immunological nonresponsiveness resulting in tumor outgrowth, even in the presence of continued B7-1 expression, are potential difficulties associated with this therapeutic approach.

    M3 - Article

    VL - 3

    SP - 321

    EP - 330

    JO - Cancer Gene Therapy

    JF - Cancer Gene Therapy

    SN - 0929-1903

    IS - 5

    ER -