The goal of this project is to investigate the biology and mechanisms of action of a gene that was recently identified in mature dendritic cells. Our initial analyses show that is highly upregulated and leads to apoptosis in mature DCs. The central hypothesis these studies will test is that this gene termed MINOR (mitogen inducible nuclear orphan receptor) is part of a pathway designed to induce apoptosis in mature DCs, thereby limiting the immune response, and that we can manipulate this pathway to enhance immune responses to tumors. MINOR is a member of the Nur 77 family, which is known to induce apoptosis in T cells. While MINOR is highly expressed in DCs, Nur 77 is not, thus we have set forth the hypothesis that MINOR plays an analogous apoptosis-inducing role in mature DCs. Stimulation of potent, durable immune responses is a major goal of vaccination, whether for immunization against pathogens or tumor cells. DCs are required for priming naive T cells and are recognized for their potent immune stimulatory effects. As a result, a number of studies have investigated their use in cancer therapies, primarily by generating DCs ex vivo followed by reinfusion. While these studies have shown great promise, they have met with limitations, which partly result from the short lifespan of DCs in vivo. We have been developing an approach to prolong survival and immune stimulation through inhibiting a novel gene expressed in mature DCs that induces apoptosis. We have developed a lentiviral vector that contains a small interfering RNA against MINOR. MINOR expression is upregulated in mature DCs, which makes it an ideal target for inhibiting apoptosis. Results of our studies show that siRNA mediated inhibition of this gene expression leads to enhancement of ex vivo generated DC vaccine potency. Further, in our gene-modified bone marrow transplant setting in which hematopoietic stem cells are transduced with siRNA prior to transplantation, we generate an increase in live DC populations. The goals of the proposed studies are to further investigate the function of this gene and to evaluate the effect of manipulating its expression in improving tumor vaccines.
| Lebson, L; Wang, T; Jiang, Q et al. (2011) Induction of the glucocorticoid-induced leucine zipper gene limits the efficacy of dendritic cell vaccines. Cancer Gene Ther 18:563-70 |
| Lebson, Lori; Gocke, Anne; Rosenzweig, Jason et al. (2010) Cutting edge: The transcription factor Kruppel-like factor 4 regulates the differentiation of Th17 cells independently of ROR?t. J Immunol 185:7161-4 |
| Wang, Tianhong; Jiang, Qiong; Chan, Camie et al. (2009) Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR. Blood 113:2906-13 |
