Gene therapy with modified tumor cells enables T-cell activation by stimulating pathways required for signal transduction.

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.