Effective anti-tumor immunity requires the generation and persistence of functional, high avidity tumor-specific effector and memory T cells. Among the critical factors that often control this response is the activation/differentiation state of the relevant effector T-cells. We have made the singular observation that IL- 12 conditioning during in vitro priming is able to promote the acquisition of a central memory (Tcm) like phenotype in antigen-specific T cells. These """"""""early activated"""""""" T (TEA) cells are characterized by increased expression of lymph node (LN) homing receptors, robust proliferation in vitro, an augmented survival, and increased anti-tumor activity in vivo. We have also recently observed that cyclophosphamide (CTX) preconditioning induces expansion of immature DCs mainly in the peripheral blood during the rebound phase which is associated with highly effective anti-tumor responses in vivo. With an interest in capitalizing on the combined potential of these observations, we hypothesize that the enhanced survival and function of IL- 12 pre-conditioned TEA cells will result in the generation of more effective anti-tumor immunity when combined with a surging frequency of circulating DCs. To test this hypothesis we propose to define how IL-12 pre-conditioning enhances T-cell survival and function (looking at co-stimulation signature, survival signaling, and impact on functional avidity) and define the TEA cell response to antigen presentation in a DC rich environment (looking specifically at the contribution of secondary lymphoid compartments. The ability to understand and harness the combined potential of early activated T cell generation and robust circulating DC induction could serve to synergistically augment in the generation of an effective anti-tumor response in vivo. The two year ARRA funding mechanism will allow us to address the first aspect of this goal by defining how IL-12 conditioning enhances antigen experienced T-cell survival and function.
Our focus is to generate new and more effective ways to treat cancer. Understanding the mechanisms behind the generation of effective anti-tumor immune responses will provide the scientific basis for novel clinical strategies leading to the design of more effective immunotherapy protocols.
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