Irradiated NC Adenocarcinoma Cells Transduced with Both B7.1 and Interleukin-2 Induce CD4+-Mediated Rejection of Established Tumors

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Abstract
Previous studies have shown that expression of the immune co-stimulator B7.1 reduces the tumorigenicity of some, but not all, malignant cell lines. However, B7.1-expressing tumor cells are not very effective in inducing the rejection of established tumors. This may in part be due to induction of anergy in the potentially reactive T cells. Previous studies have shown that IL-2 can reverse the anergic state both in vitro and in vivo. Therefore, we have examined the effect of retrovirus-mediated delivery and expression of murine B7.1 and interleukin-2 on tumor formation and rejection of established MHC class I+/II¯ NC adenocarcinomas. Neither the expression of B7.1 nor IL-2 alone had a significant effect on NC tumorigenicity. In contrast, combined expression of B7.1 and IL-2 substantially decreased the tumorigenicity of these cells in the immune-competent syngeneic hosts. T-cell depletion studies show this to be dependent primarily on the activation of CD4+ cells. Furthermore, distant subcutaneous injection of irradiated NC/IL-2/B7.1 can induce, much more effectively than NC/B7.1 or NC/IL-2, the rejection of small NC tumors, and prevent the recurrence of large surgically resected tumors. Together, these results suggest that tumor cells genetically modified to express B7.1 and IL-2 can induce the immune-mediated rejection of established class II¯ tumors by a mechanism involving CD4+ cells. Previous studies have shown that expression of the immune co-stimulator B7.1 can induce the rejection of some, but not all, murine tumors. In this study, we show that expression of B7.1 by itself has no effect on the tumorigenicity of NC murine adenocarcinoma cells. Similarly, expression of interleukin-2 (IL-2) alone has little effect on the tumorigenicity of these cells. By contrast, the combined expression of B7.1 and IL-2 substantially reduces the tumorigenicity of NC cells, and irradiated NC/B7.1/IL-2 cells are able to induce the rejection of previously established NC tumors. These results suggest a much greater therapeutic potential for tumor cell vaccines that express both B7.1 and IL-2 rather than either of the immune modulators alone.