Therapeutic cancer vaccines are intended to drive specific activation of the immune system for therapy of existing malignancies or prevention of their recurrence. This requires powerful vaccination strategies, due to the preexisting immunosuppressive mechanisms orchestrated by the tumor. Theoretically, vaccination with apoptotic autologous tumor cells represents a particularly promising way to target the greatest number of potential antigens without the need for their individual identification. However, the sensing and clearance of apoptotic cells is generally considered to be a non-inflammatory or even tolerizing process. The prevailing view has been that apoptotic cells generated by normal tissue turnover are captured by dendritic cells (DCs) that migrate to local lymph nodes, where they induce T cell tolerance, T cell anergy, or T cell deletion in order to maintain tissue homeostasis and prevent autoimmunity in the host. We recently identified a novel DC subset (nDC), that, in contrast with other cross-presenting and cross-tolerizing DC subsets, potently (cross-)primes both CD4+ and CD8+T cells to cell-associated antigens after uptake of apoptotic material. The potent adjuvant activity of the nDC is largely dependent on their production of type I IFN after interacting with apoptotic cells. T cells primed by nDC display a greater capacity for primary expansion, cytokine production, and memory formation on a per cell basis than those primed by other DC subsets. As a consequence, these nDC are extremely potent in the induction of protective anti- tumor responses in both vaccination and therapeutic settings when exposed to apoptotic tumor cells. The central hypothesis underlying our proposed studies is that type I IFN production by nDC exposed to apoptotic cells is critical for nDC function and their subsequent priming of protective T cell responses to cell-associated antigens. The long-term goals of this work are two-fold: (1) definition of the molecular and cellular mechanisms in DCs that balance the pro- and anti-inflammatory immune response to self after cell death;and (2) translational exploitation of these mechanistic insights in order to devise effective therapeutic and preventive cancer vaccines.

Public Health Relevance

Vaccination with apoptotic autologous tumor cells represents a particularly promising way to target the greatest number of potential antigens without the need for their individual identification. However, Cross- presentation of cell-associated antigens from apoptotic cells by DC generally leads to the induction of T cell tolerance. We have identified a new DC subset that is capable to prime T cells to cell associated antigen. In this project we will define the molecular and cellular mechanisms in these DCs that confer the T cell priming capacity in order to translational exploit of these mechanistic insights for the design of effective therapeutic and preventive cancer vaccines. .

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138617-05
Application #
8447368
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2009-04-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$283,799
Indirect Cost
$94,600
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Zhang, Xue; Ulm, Ashley; Somineni, Hari K et al. (2014) DNA methylation dynamics during ex vivo differentiation and maturation of human dendritic cells. Epigenetics Chromatin 7:21
Klarquist, Jared; Hennies, Cassandra M; Lehn, Maria A et al. (2014) STING-mediated DNA sensing promotes antitumor and autoimmune responses to dying cells. J Immunol 193:6124-34
Nierkens, Stefan; den Brok, Martijn H; Garcia, Zacharias et al. (2011) Immune adjuvant efficacy of CpG oligonucleotide in cancer treatment is founded specifically upon TLR9 function in plasmacytoid dendritic cells. Cancer Res 71:6428-37
Hennies, C M; Reboulet, R A; Garcia, Z et al. (2011) Selective expansion of merocytic dendritic cells and CD8DCs confers anti-tumour effect of Fms-like tyrosine kinase 3-ligand treatment in vivo. Clin Exp Immunol 163:381-91
Daissormont, Isabelle T M N; Christ, Anette; Temmerman, Lieve et al. (2011) Plasmacytoid dendritic cells protect against atherosclerosis by tuning T-cell proliferation and activity. Circ Res 109:1387-95
Yamaguchi, Ryuji; Janssen, Edith; Perkins, Guy et al. (2011) Efficient elimination of cancer cells by deoxyglucose-ABT-263/737 combination therapy. PLoS One 6:e24102
Reboulet, Rachel A; Hennies, Cassandra M; Garcia, Zacarias et al. (2010) Prolonged antigen storage endows merocytic dendritic cells with enhanced capacity to prime anti-tumor responses in tumor-bearing mice. J Immunol 185:3337-47