Advances in our understanding of human dendritic cells have resolved many important unknowns about the onset of innate and adaptive immunity and how dendritic cells can control these responses against tumor antigens. The increasingly recognized diversity of human dendritic cell subtypes has also led to a more heterogeneous, and probably more realistic picture of various dendritic cell functions. Some of these findings solve longstanding unknowns, while others compel us to reexamine the accuracy of accepted models. The resulting questions comprise the basis of our planned studies. We hypothesize that distinct human dendritic cell subtypes achieve the most effective tumor immunity by coordinating the activation of NK and NKT cells, with the stimulation of adaptive, MHC-restricted and antigen-specific T cell immunity. We will compare distinct populations of monocyte-derived dendritic cells with Langerhans cells or dermal-interstitial dendritic cells generated from CD34+ progenitors to test this unifying concept of dendritic cell-induced tumor immunity in the following specific aims.
Aim 1 will determine the cytokines secreted by different dendritic cell subtypes that are critical to the stimulation of NK, NKT, and effector memory T cells, especially CD8+ CTL, focusing on the activity of IL-15 vs IL-7 vs IL-2, and IL-23 vs IL-12;
Aim2 will define the biologic mechanism(s) by which mature, rather than immature dendritic cells activate indoleamine 2,3-dioxygenase, which can suppress the immune response against tumor antigens;
and Aim 3 will establish whether antibody-opsonization salvages tumor antigen from the terminally degradative pathway for presentation on CD1d or MHC to NKT or T cells respectively. These studies will define new biologic rationales for the use of dendritic cell subtypes, either in combination or in a prime-boost sequence, to generate both innate and adaptive immune responses and hence more effective overall tumor immunity. (Relevance to Public Health / Lay Summary: Specialized white blood cells, called dendritic cells, are key stimulators of the immune system. Dendritic cells comprise different subsets with potentially very useful differences in function. These studies will investigate the biologic mechanisms by which dendritic cell subsets alone and in combination can stimulate immunity against cancer, which is a major public health problem. New and improved approaches for the immune-based treatment of cancer are anticipated, with the most effective application likely being the treatment of minimal residual disease after primary therapy.)

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Howcroft, Thomas K
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Sloan-Kettering Institute for Cancer Research
New York
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Curran, Shane A; Shyer, Justin A; St Angelo, Erin T et al. (2017) Human Dendritic Cells Mitigate NK-Cell Dysfunction Mediated by Nonselective JAK1/2 Blockade. Cancer Immunol Res 5:52-60
Curran, Shane A; Romano, Emanuela; Kennedy, Michael G et al. (2014) Phenotypic and functional activation of hyporesponsive KIRnegNKG2Aneg human NK-cell precursors requires IL12p70 provided by Poly(I:C)-matured monocyte-derived dendritic cells. Cancer Immunol Res 2:1000-10
Chung, David J; Romano, Emanuela; Pronschinske, Katherine B et al. (2013) Langerhans-type and monocyte-derived human dendritic cells have different susceptibilities to mRNA electroporation with distinct effects on maturation and activation: implications for immunogenicity in dendritic cell-based immunotherapy. J Transl Med 11:166
Romano, Emanuela; Cotari, Jesse W; Barreira da Silva, Rosa et al. (2012) Human Langerhans cells use an IL-15R-?/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1. Blood 119:5182-90
Betts, Brian C; Abdel-Wahab, Omar; Curran, Shane A et al. (2011) Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen. Blood 118:5330-9
Romano, Emanuela; Rossi, Marco; Ratzinger, Gudrun et al. (2011) Peptide-loaded Langerhans cells, despite increased IL15 secretion and T-cell activation in vitro, elicit antitumor T-cell responses comparable to peptide-loaded monocyte-derived dendritic cells in vivo. Clin Cancer Res 17:1984-97
Betts, Brian C; St Angelo, Erin T; Kennedy, Michael et al. (2011) Anti-IL6-receptor-alpha (tocilizumab) does not inhibit human monocyte-derived dendritic cell maturation or alloreactive T-cell responses. Blood 118:5340-3
Bamboat, Zubin M; Stableford, Jennifer A; Plitas, George et al. (2009) Human liver dendritic cells promote T cell hyporesponsiveness. J Immunol 182:1901-11
Strowig, Till; Gurer, Cagan; Ploss, Alexander et al. (2009) Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J Exp Med 206:1423-34
Chung, David J; Rossi, Marco; Romano, Emanuela et al. (2009) Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood 114:555-63

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