Regulatory T cells (Treg) suppress autoreactive immune responses and limit the efficacy of tumor vaccines;however, it remains a challenge to selectively eliminate or inhibit Treg and other regulatory cells. In our recent studies supported by the current grant (1R01CA090427;7/2002-6/2007), we found that A20, a negative regulator of the TLR and TNFR signaling pathways, critically restricts the maturation, cytokine production, and immunostimulatory potency of dendritic cells (DC). A20-silenced DCs expressed enhanced levels of proinflammatory cytokines and costimulatory surface molecules. A20-silenced DCs had contrasting effects on T cell subsets, namely inhibiting Treg but hyperactivating CTLs and Th that were more refractory to Treg-mediated suppression, leading to enhanced antitumor immunity in mice. The results of this study provide a novel strategy to supersede Treg- mediated suppression in an antigen-specific manner. In this continuation study, we aim to develop more potent tumor vaccines capable of overcoming immune suppression. The central hypothesis of this continuation study is that inhibition of A20 and integrin av/?8 or neuropilin, which is required for TGF? activation, and stimulation with TLR5 agonist uniquely triggers and sustains TLR signaling cascades to endow DCs with the unique capacity to inhibit Treg and hyperactivate antitumor CTL/Th cells.
The specific aims are: 1. to test whether DCs that are transduced to coexpress the inhibitor of TLR's negative regulator A20 (shA20) and secretory flagellin (FliC), TLR5 ligand, to uniquely trigger and sustain TLR signaling cascades can efficiently stimulate the effector phase of antitumor memory responses to tip the balance from immunosuppression to antitumor immunity in tumor-bearing mice. 2. to test the hypothesis that silencing of integrin av/?8 or neuropilin (Nrp) 1 blocks the ability of DCs to activate latent TGF-?, reducing their ability to induce Foxp3 expression and convert conventional T cells into Treg cells. And 3. to test the hypotheses that murine and human DCs that coexpress FliC and shRNAs of both A20 and integrin av/?8 or Nrp1 induce potent antitumor responses capable of overcoming Treg suppression and have a unique ability to persistently stimulate adoptively transferred T cells for combinational immunotherapy. The significance of this study is twofold: first, this study may lead to the development of more potent tumor vaccines capable of overcoming immunosuppression with the potential of clinical applications;second, this study contributes to the basic understanding of molecular and cellular mechanisms that critically regulate antigen presentation, immunosuppression, and antitumor immunity.
In this continuation study, we aim to develop more potent tumor vaccines capable of overcoming immune suppression. Specifically, we will test whether inhibition of the negative regulator A20 and stimulation with TLR agonists will allow dendrite cells to induce effective antitumor immunity, leading to more potent tumor immunotherapy.
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