In this application we propose a novel strategy for development of effective tumor vaccines by modifying STAT3 activity in dendritic cells (DCs). This strategy is based on our recent progress in understanding roles of STAT proteins, STAT3 in particular, in DC function and differentiation. We have developed a unique animal model for studies of immune responses and immune tolerance using STAT3 deficient (STAT3-/-) dendritic cells and mice. We have found that STAT3 is specifically required for FltSL-mediated DC differentiation. However, the deficiency in dendritic cell differentiation in STAT3-/- mice could be partially rescued by GM-CSF, which activated other STAT proteins, STAT3 particularly. However, generation of plasmacytoid dendritic cells (pDC) was highly dependent on STAT3. We suggest that the lack of STAT3 activity and the loss of pDC may contribute to reduction of immune tolerance in the STAT3-/- mice. Our results suggest a critical mechanism of regulation of immune tolerance. Using this STAT3 deficient mouse model we will be able to study roles of STAT3 in dendritic cells as well as in lymphocytes, providing a powerful tool for dissecting mechanisms of both innate immunity and adaptive immunity systematically. Our KO mice are probably the only animal model system in which STAT3 is ablated during physiological development of dendritic cells. In this application we will study roles of STAT3 in antigen presentation and tumor vaccination. Our major hypothesis is that STAT3 regulates generation of tolerogenic dendritic cells and that inhibition of STAT3 activity will stimulate stronger immune responses that will facilitate development of an effective immune response in tumor vaccination.
Specific Aim 1) To investigate whether STAT3 affects tumor antigen presentation in DCs and whether blocking of STAT3 in DC-facilitated vaccine will enhance anti-tumor immune response in vivo;
Specific Aim 2) To investigate the possible mechanisms how STAT3 can modulate immune responses and the efficacy of DC-facilitated tumor vaccine.
Specific Aim 3) To examine roles of STAT3 in a mouse model in which a prostate cancer could be developed due to tumor tolerance. We hypothesize that the loss of STAT3 in DCs will increase T cell responses against the tumor development. The interactions of these immune cells with tumor cells in presence or absence of STAT3 will be systematically examined. These proposed studies should reveal novel molecular and cellular mechanisms by which STAT3 controls innate and adaptive immune responses during vaccination. We believe that this project will provide novel rationale and concepts for development of therapeutics for human cancers as well as other immune disorders.
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|Do, Dang Vinh; Ueda, Jun; Messerschmidt, Daniel M et al. (2013) A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo. Genes Dev 27:1378-90|