Tumor cells cotransfected with interleukin‐7 and B7.1 genes induce CD25 and CD28 on tumor‐infiltrating T lymphocytes and are strong vaccines

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Abstract
Interleukin‐7 (IL‐7) and the membrane molecule B7 are both able to provide proliferation and activation signals for T cells. However, tumor cells transfected to express either molecule alone are not reliably rejected in syngeneic hosts or are not sufficiently immunogenic to serve as potent tumor vaccines. Since IL‐7 and B7 have shown synergistically to induce activation and proliferation of T cells in vitro, we have expressed B7.1 by means of a retrovirus in the mammary adenocarcinoma TS/A which arose spontaneously in a BALB/c mouse and in the plasmacytoma J558L and their IL‐7‐transfected sublines to improve vaccine efficacy. Expression of IL‐7 or B7.1 alone in tumor cells decreased tumorigenicity, but nevertheless tumors grew in a substantial number of mice. In contrast, IL‐7/B7.1 cotransfected cells did not grow as tumor in a single case. This inhibition of tumor growth was completely T cell dependent, because TS/A‐IL‐7/B7.1 cells retained their full tumorigenic potential in T cell‐deficient mice. Analysis of tumor‐infiltrating T lymphocytes revealed increased numbers of T cells in B7, IL‐7 and IL‐7/B7 transfected compared to parental tumors. In IL‐7/B7 transfected tumors, T cell numbers were not further increased compared to that in singlegene‐transfected tumors. However, T cells in B7 and IL‐7 transfected tumors differed phenotypically with respect to activation markers. In B7 transfected tumors, T cells were predominantly CD28+ and CD25+, while in IL‐7‐transfected tumors, T cells were mainly CD28− and CD25+. In IL‐7/B7 cotransfected tumors, the majority of T cells was CD28+ and CD25+. Thus, IL‐7 and B7 induced an anti‐tumor immune response by complementary T cell directed pathways in a cooperative fashion. Importantly, immunization of mice with the transfected cells and subsequent contralateral challenge with parental tumor cells showed that IL‐7/B7 co‐expressing cells induced the most strongly protective immunity, which is superior to that induced by single‐gene transfectants and to the adjuvant Corynebacterium parvum. Vaccine efficacy was abrogated when irradiated cells were used for vaccination. Together, our results show that IL‐7 and B7.1 transfected tumor cells induce strong T cell activation and tumor immunity.