Plasmacytoid DC Interactions in the Generation of an Antitumor Immune Response

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DESCRIPTION (provided by applicant): Although the immune response against viral infections is generally potent, naturally generated antitumor immune responses are often weak by contrast. Applying the components of antiviral immune responses to tumor immunology is a potentially promising strategy towards the generation of a more effective antitumor response. Strong adaptive, cytotoxic T cell (CTL)-mediated immune responses are known to be dependent on initial activation of the innate immune system. Plasmacytoid dendritic cells (pDCs), a subset of innate immune cells that produce high levels of type I interferons on viral stimulation, play a central role in modulating innate and adaptive immunity against viral infections. In this proposal, we will systematically evaluate the mechanisms by which pDCs can induce augmented CTL-mediated antitumor responses through their interactions with conventional myeloid dendritic cells (mDCs) and natural killer (NK) cells. In our preliminary studies, we found that activated, antigen-pulsed, pDC and mDC could individually stimulate antigen-specific CTL responses in mice. However, immunization with a mixture of activated pDCs and mDCs led to a markedly enhanced induction of antigen-specific CTLs resulting in an improved antitumor response, which we hypothesize is due to augmentation of mDC activation by pDCs. In addition, we found that activated pDCs are capable of activating NK cells in vitro and in vivo and may also stimulate NK cell chemotaxis. Importantly, intratumoral injection of activated pDCs resulted in the in vivo cross-priming of tumor antigen-specific CTLs in an NK cell-dependent manner. We hypothesize that pDC-mediated activation of NK cells resulted in increased tumor cell lysis and subsequent uptake and cross-presentation of tumor antigen by locally activated mDCs, leading to tumor antigen-specific CTL priming. In the following Specific Aims, we propose to define the mechanisms of these cellular interactions in order to ultimately apply these concepts to the generation of a more successful antitumor immune response in patients: (1) Characterize the interactions between pDC and mDC that underly their synergy in the induction of antigen-specific T-cells (2) Determine the mechanisms by which pDCs and NK cells can augment T-cell cross-priming against tumor-derived antigens. (3) Define the molecular mechanisms through which pDCs induce mDC maturation and NK cell activation and accumulation.