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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA123182-01
Application #
7139030
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2006-08-15
Project End
2011-07-31
Budget Start
2006-08-15
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$266,250
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Liu, Chengwen; Lou, Yanyan; Lizee, Gregory et al. (2008) Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest 118:1165-75