Gene therapy with modified tumor cells enables T-cell activation by stimulating pathways required for signal transduction.
The expression of a variety of stimulatory molecules by tumor cells can lead to tumor rejection and the development of systemic immunity by T cells. The fact that some tumor cells naturally express such determinants leads to the hypothesis that progressive tumor growth may be a reflection of problems with the host immune system. To test this, we compared the signal-transducing ability of T cells from mice inoculated with parental tumors (PTB) with that of T cells from mice immunized with IL-2-secreting tumor cells (ITB). Our results demonstrated that following T-cell activation, higher total kinase activity was associated with the signal-transducing zeta chain in ITB mice compared with PTB mice. Western blotting following stimulation of T cells with parental or genetically engineered IL-2-secreting, B7+ tumor cells revealed increased protein tyrosine phosphorylation in lysates derived from ITB compared with PTB T cells, demonstrating that tumor-derived IL-2 could influence signaling. Taken together, the findings are consistent with the hypothesis that tumor-derived IL-2 preserves the signal-transducing ability of immunocompetent T cells, but is ineffective when they are immunosuppressed. These results suggest that IL-2-secreting tumor cell vaccines might be useful as adjuvant therapy to prevent the outgrowth of micrometastases, following tumor resection, once immune function has normalized.
Salvadori
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Division of Clinical Immunology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Zier
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K
D000818:Animals; D005354:Fibrosarcoma / Q000276:immunology / Q000628:therapy*; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase
D007376:Interleukin-2; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse