Strong adaptive immunity depends on a strong innate immune response triggered by pathogen-derivedmolecules, such as Toll-Like Receptor (TLR) ligands. Current cancer vaccines typically induce tumor-specificT cells but no tumor regression. This may be because tumors are deficient in TLR ligands, reducing innateimmune activation in tumors and thereby limiting the priming, accumulation, in situ activation and anti-tumoreffector function of tumor-specific T cells. Plasmacytoid Dendritic Cells (pDCs) are cells of the innateimmune system that critically orchestrate both innate and adaptive immune responses. pDCs have beenfound inside human tumors and are therefore potentially ideal targets for therapeutic intervention with TLR7and TLR9 agonists which activate pDCs. However, it is unknown whether intratumoral pDCs are activated orwhether they can respond to TLR agonist stimulation in vivo, and what the downstream effects of suchactivation are for innate and adaptive anti-tumor immunity. In addition, little is known about the mechanismthrough which pDCs could stimulate innate and adaptive anti-tumor immunity in vivo. Since immuneresponses are complex, they can only be fully understood through in vivo studies. We have developed amouse model that allows us to study the presence and function of pDCs in tumors in vivo. We found thatnon-activated pDCs were present in murine melanoma. TLR agonist-activated pDCs could activateconventional mDCs, enhancing their capacity to prime tumor-specific T cells in vivo. Furthermore, activatedpDCs potently activated NK cells in vivo to induce tumor destruction and de novo priming of additional tumorspecificCD8+ T cells. Building on the gplOO-specific TCR transgenic pmel-1 mouse model we havepreviously developed, we also found that in vivo activation of pDCs with TLR agonists enhanced tumorregression mediated by vaccine-induced, gplOO-specific CD8+ T cells. Based on these data we hypothesizethat activation of intratumoral pDCs by TLR agonists in vivo will result in activation of mDCs and NK cells inthe tumor leading to the induction of potent innate and adaptive anti-tumor immune responses. To test thishypothesis we will activate intratumoral pDCs in vivo with TLR agonists and test their ability to activatemDCs and NK cells and to induce the accumulation of tumor-specific T cells and tumor destruction, throughthe following Specific Aims:
Specific Aim 1. Characterize the ability of intratumoral pDCs to interact with mDCs.
Specific Aim 2. Evaluate the interactions between intratumoral pDCs and NK cells.
Specific Aim 3. Determine whether intratumoral pDC activation by TLR agonists enhances T cellmediatedanti-tumor function.Our goal is to identify principles which may be generalized towards improving immunotherapy of cancerpatients.
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