Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
In order to induce significant tumor regression T cells must effectively recognize and kill target cells. Secretion of IFN-γ is considered a key effector function of activated CD8+ T cells via induction of apoptosis. Thus programming T cells to secrete high levels of IFN-γ after adoptive transfer could represent a therapeutically effective anti-cancer intervention.
We previously demonstrated that naïve CD8+ T cells exposed to IL-12 during antigenic priming (PmelAg+12) provided superior anti-tumor activity after transfer when compared to cells activated in the presence of antigen alone (PmelAg). In this setting, tumor regression was associated with sustained levels of intra-tumoral IFN-γ. Expression analysis using total tumor RNA showed elevated expression of IFN-γ responsive genes such as IP-10, MCP-1, MIG, and MIP-1α. 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-γ. However, by day 7 after adoptive transfer tumors in mice that received PmelAg were significantly larger than those in mice injected with PmelAg+12. Failure to maintain intra-tumoral levels of IFN-γ was associated with a decrease in the frequency of tumor infiltrating PmelAg. We hypothesized that high levels of IFN-γ had a detrimental effect on PmelAg, via induction of apoptosis. IFN-γ is a multifunctional cytokine that induces a variety of contrasting cell responses such as proliferation or cell death. The cellular response to an IFN-γ stimulus depends on the specific receptor being activated, with IFN-γR1 inducing proliferation and IFN-γR2 inducing apoptosis.
We tested the hypothesis that the ability of T cells to survive in vivo after adoptive transfer was dependent on their susceptibility to IFN-γ-induced apoptosis. Real time PCR revealed that the expression levels of IFN-γR1 and IFN-γR2 immediately following antigen or antigen+ IL-12 priming were similar, though by 4d post adoptive transfer the tumor-infiltrating Pmel cells stimulated with antigen alone had 10 fold higher levels of IFN-γR2 than tumor associated PmelAg+IL-12.
These results suggest that the enhanced anti-tumor activity of PmelAg+IL-12 might be due to their decreased sensitivity to IFN-γ-induced apoptosis. Thus inhibiting IFN-γ-induced activation induced cell death (AICD) by down-regulating IFN-γR2 expression on T cells may represent a novel mechanism by which IL-12 enhances anti-tumor activity.