IFN-gamma is Central to Both Immunogenic and Tolerogenic Properties of Dendritic Cells After IL-12 and GM-CSF Microsphere Treatment
Harden, Jamie L.
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A single intra-tumoral injection of IL-12 and GM-CSF microspheres results in tumor regression and initiation of an anti-tumor immune response. Activation of NK cells and CD8+ T-cells along with a decrease in T-regulatory cells, after treatment have been observed. The anti-tumor effects of GM-CSF and IL-12 microsphere treatment have been shown to be dependent on IFN-gamma. However, further studies demonstrated that the immune response was transient and that the T-regulatory cells rebounded rapidly. Recent data from our laboratory suggested that indoleamine 2, 3 -dioxygenase (IDO), an IFN-gamma-inducible immune-suppressive enzyme, may play a role in the post-therapy T-regulatory cell resurgence. Since dendritic cells (DCs) are central to both induction of an immune response, and have been shown to be significant producers of IDO, the effect of IL-12 and GM-CSF microsphere treatment on this potent antigen presenting cell was explored. We found that intra-tumoral injection of IL-12 and GM-CSF microsphere resulted in rapid recruitment of DC to tumors with subsequent migration to tumor-draining lymph nodes (TDLN). Post-treatment DCs displayed increased CD86 expression, a pro-inflammatory cytokine profile and effective CD8+ and CD4+ T-cell priming in vitro (immunogenic). By Day 7 post-treatment however, the priming ability of these DCs was completely lost (tolerogenic). Further analysis revealed that day 7 DCs expressed high levels of IDO, inhibition of which resulted in the rescue of the ability to prime T-cells. GM-CSF and IL-12 mediated induction of immunogenic DCs was completely abrogated in IFN-gamma knockout mice, establishing the critical role of this cytokine in post-therapy immune activation. Importantly, TDLN DCs failed to upregulate IDO and IDO-inhibition did not restore priming function to day 7 DCs in IFN-gamma knockout mice, revealing that IFN-gamma was also responsible for the induction of tolerogenic function in DCs. These results establish the dichotomous role of IFN-gamma in the regulation of IL-12-mediated antitumor immunity and identify DC as the primary conduit that mediate these effects. Furthermore, these data support the hypothesis that blocking IDO in therapeutic regimen designed to induce T H 1 responses may prove useful by extending the window of T-cell priming and activation.