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Gene therapy with modified tumor cells enables T-cell activation by stimulating pathways required for signal
1Division of Clinical Immunology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Abstract:
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.
Insights
Tumor-derived interleukin-2 (IL-2) enhances T-cell signaling, promoting tumor rejection. This suggests IL-2 secreting tumor cells could be an effective adjuvant therapy for preventing cancer recurrence.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Signaling
Background:
- Tumor cells can express molecules that trigger T-cell mediated immunity.
- Progressive tumor growth may indicate immune system deficiencies.
- Interleukin-2 (IL-2) plays a crucial role in T-cell activation and proliferation.
Purpose of the Study:
- To investigate the impact of tumor-derived IL-2 on T-cell signal transduction.
- To compare the T-cell signaling capacity between mice with parental tumors and those immunized with IL-2-secreting tumors.
Main Methods:
- Comparison of T-cell signal transduction in mice inoculated with parental tumors (PTB) versus IL-2-secreting tumor cells (ITB).
- Analysis of total kinase activity associated with the zeta chain after T-cell activation.
- Western blotting to assess protein tyrosine phosphorylation in T-cell lysates following stimulation with different tumor cell types.
Main Results:
- T cells from ITB mice exhibited higher total kinase activity associated with the zeta chain post-activation compared to PTB mice.
- Increased protein tyrosine phosphorylation was observed in T cells from ITB mice stimulated with IL-2-secreting tumor cells.
- Tumor-derived IL-2 was shown to influence T-cell signaling pathways.
Conclusions:
- Tumor-derived IL-2 preserves the signal-transducing ability of immunocompetent T cells.
- The effectiveness of tumor-derived IL-2 is diminished in immunosuppressed individuals.
- IL-2-secreting tumor cell vaccines show potential as adjuvant therapy to prevent micrometastasis after tumor resection and immune normalization.