Ex vivo conditioning with IL-12 decreases T cell sensitivity to intratumoral INF-γ-induced apoptosis following adoptive transfer

Methods We previously demonstrated that naive CD8 T cells exposed to IL-12 during antigenic priming (Pmel) provided superior anti-tumor activity after transfer when compared to cells activated in the presence of antigen alone (Pmel). In this setting, tumor regression was associated with sustained levels of intra-tumoral IFN-g. Expression analysis using total tumor RNA showed elevated expression of IFN-g responsive genes such as IP-10, MCP-1, MIG, and MIP-1a. Even without IL-12 stimulation during ex vivo antigenic priming, Pmel cells were able to initially reach the tumor and secrete high levels of IFN-g. However, by day 7 after adoptive transfer tumors in mice that received Pmel were significantly larger than those in mice injected with Pmel. Failure to maintain intra-tumoral levels of IFN-g was associated with a decrease in the frequency of tumor infiltrating Pmel. We hypothesized that high levels of IFN-g had a detrimental effect on Pmel, via induction of apoptosis. IFN-g is a multifunctional cytokine that induces a variety of contrasting cell responses such as proliferation or cell death. The cellular response to an IFN-g stimulus depends on the specific receptor being activated, with IFN-gR1 inducing proliferation and IFN-gR2 inducing apoptosis.