The tumorigenicity of transplantable tumor cells in mice is reduced by transduction with cytokine genes, including IFN-α and interleukin (IL) 12. Although T cells are considered important in tumor rejection, the mechanism by which genetically modified tumor cells stimulate the immune system has not been examined. In this study, the in vivo proliferation of T-cell subsets in mice transplanted with cytokine-producing syngeneic tumor cells was assessed by administering the DNA precursor bromodeoxyuridine. The injection of viable cells producing IFN-α or IL-12 caused a marked proliferation of CD8+ T lymphocytes in both the spleen and lymph nodes. Proliferation was most prominent among memory-phenotype CD44hi CD8+ T cells. In contrast, proliferation of CD8+ T cells did not occur in mice injected with control cells or with cells expressing IL-4, granulocyte colony-stimulating factor, or IFN-γ. Pulse-chase studies in mice injected with IFN-α-producing cells showed that a proportion of proliferating CD8+ T cells survived for at least 70 days, suggesting that long-lived memory cells are induced using such an approach. In summary, these results, together with previous studies on the host immune reactivity triggered by the injection of tumor cells expressing IFN-α, represent a strong rationale for considering IFN-α as a powerful T-cell adjuvant for the generation of more effective cancer vaccines.

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Supported in part by grants from the Associazione Italiana Ricerca sul Cancro (Milan), the Italy-USA Special Project on “Therapy of Tumors,” and the USPHS. D. F. T. is the recipient of a Centennial Fellowship from the Medical Research Council of Canada.

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