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.
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.
Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre, Nedlands, Australia.
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C
Leong
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J
Marley
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Loh
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Robinson
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M
Garlepp
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005802:Genes, MHC Class II / Q000235:genetics*; D007114:Immunization; D007371:Interferon-gamma / Q000494:pharmacology; D008654:Mesothelioma / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured
D018122:B7-1 Antigen; D007371:Interferon-gamma