Our long-term goal is to develop vaccine strategies that lead to activation and expansion of therapeutic effector T cells in vivo to levels above the threshold required for tumor eradication and prevention of recurrence in tumor-bearing hosts. The objective of this proposal, is to evaluate the effect of Toll-like receptor triggering on cross-presentation of tumor antigens by DC, priming of antitumor T-cell responses and antitumor efficacy in reconstituted lymphopenic mice (RLM) bearing established tumors. Priming of antigen-specific T cells for antigens derived from either viral, intracellular bacterial pathogens or tumor cells is now known to occur via the same cross-priming pathways of host dendritic cells. For most bacterial and viral infections, the robust innate and adaptive immune responses generally result in control of infection and development of a strong memory response. In contrast, for patients with cancer, the host immune system often fails to control the growth of cancer despite the fact that tumor cells replicate at a much slower rate than bacteria and viruses. The major differences between the immunology of infection and tumors include the following: tumor cells lack strong antigens; and tumor cells do not elicit a strong proinflammatory response (innate immunity), which orchestrates the subsequent adaptive immune response. To compensate the weak immunogenicity and break the tolerance of tumor self/normal antigens, vaccination will be performed in the reconstituted lymphopenic hosts in which T-cell activation threshold is reduced due to the homeostasis-driven proliferation of naive T cells. To mimic the innate immune responses to infectious pathogens, the antigen-presenting cells, DC, that pulsed with antigens derived from tumor cells, will be activated by Toll-like receptor triggering and then used to vaccinate mice bearing either experimental melanoma or spontaneous mammary carcinoma metastases. In this proposal, these two novel strategies will be combined to test the following hypothesis: Reduced threshold for T-cell activation in lymphopenic hosts will result in optimal activation and expansion of tumor-reactive CD4+ and CD8+ T cells when tumor antigens are presented by activated mature dendritic cells.
The specific aims of this proposal are: to optimize the DC activation conditions for efficient crosspriming of tumor-specific T cells; to investigate efficacy of DC-based vaccines in RLM; to track the fate of tumor-specific CD8 T cells in RLM; to investigate how CD4-help affect the fate of tumor-specific CD8 T-cells in vaccinated RLM. ? ?
