Expression of Co-Stimulatory Molecules by Tumor Cells Decreases Tumorigenicity but May Also Reduce Systemic Antitumor Immunity

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Abstract
Many tumor cells do not express co-stimulatory molecules, and this may account, in part, for their poor ability to stimulate T cells directly. One strategy to enhance immune recognition would be to express such molecules on the tumor cell. Here, we show that expression of a member of the B7 family of co-stimulatory molecules by CMT93 murine colorectal tumor or 1735 murine melanoma cells resulted in a local antitumor response in immunocompetent mice. The antitumor effect was diminished in athymic nude mice, indicating that T cells played an important part in this response. The ability of the B7-expressing tumor cells to generate systemic protective immunity was investigated by excision of tumors that developed from the initial inoculation followed by rechallenge with parental tumor cells. CMT93 is a poorly immunogenic tumor and no significant systemic immunity was elicited by the expression of B7-1 in these cells. 1735 melanoma is a mildly immunogenic tumor. Unexpectedly, the systemic immunity obtained with 1735 tumors expressing B7-1 or B7-2 was weaker than that generated by parental 1735 cells (p < 0.001, stratified logrank test), even when co-expression of interferon-γ in the B7-1 cells produced high levels of surface MHC class I expression. These results suggest that some caution is appropriate when considering the use of these molecules in the gene therapy of cancer. In an attempt to enhance the immune recognition of tumor cells, B7 was expressed in CMT93 colorectal tumor or 1735 melanoma cells. When the B7-expressing tumor cells were inoculated into syngeneic mice, they were less tumorigenic than the parental lines. The generation of systemic protective immunity was examined by surgical excision of the primary tumor followed by rechallenging with parental tumor cells. Thus, in this model live cells were used to elicit systemic immunity, a situation that might mimic possible protocols in which a therapeutic gene is delivered directly into a tumor. Expression of B7-1 in CMT93 cells did not generate significant protective immunity. Surprisingly, the expression of B7-1 or B7-2 in 1735 cells resulted in less effective protective immunity than that elicited by the parental 1735 cells. This adverse effect has implications for the use of B7 co-stimulatory molecules in the gene therapy of cancer.