Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for many hematological malignancies resistant to other therapies. This beneficial anti-tumor activity largely derives from infused donor T cells, named graft-versus-tumor (GVT) effect. However, relapse remains a major cause of treatment failure of allo-HSCT for patients with high-risk hematological malignancies. In addition, the GVT effect lacks specificity and is tightly linked to a life-threatening complication of graft-versus-host disease (GVHD). Novel approaches are urgently needed to improve GVT while limiting GVHD after allo-HSCT. Notch signaling may play multiple important roles in peripheral T cell responses. Using mouse models of allo-HSCT, we discovered that: 1) Notch-deprived donor T cells showed drastically reduced ability to produce effector cytokines (e.g., IFN-?, TNF-? and IL-17) and failed to cause GVHD, suggesting that the Notch pathway increased on the surface of a subset of recipient dendritic cells (DCs) during GVHD induction. We named these Dll4-positive DCs as Dll4+DCs. As compared to Dll4-negative DCs (Dll4-DCs), Dll4+DCs expressed higher levels of CD80 and CD86, had increased IL6 and IL23 mRNA but reduced transcripts of IL12, IL21 and Arginase 1. Inhibition of Dll4 caused a reduction in frequency of alloreactive effector T cells activated by allogeneic DCs. Furthermore, in vivo treatment with anti-Dll4 antibody (Ab) inhibited GVHD. Thus, Dll4 activation of Notch signaling is important for GVH responses;3) Flt3L and Toll-like receptor signaling were essential for induction of Dll4+DCs from cultured bone marrow cells. Inhibition of NF-?B signaling blocked the expression of Dll4 in Flt3L-induced DCs;4) Flt3L-induced Dll4+DCs had greater ability than GM-CSF-induced Dll4-DCs to promote CD4+ T helper (Th)1 and Th17 cell differentiation. Transfer of Flt3L-induced Dll4+DCs that were loaded with tumor antigen-peptide induced potent CD8+ T cell-mediated antitumor activity. Thus, we hypothesize that Dll4+DCs are previously uncharacterized inflammatory DCs important for the induction of GVHD and GVT.
Three specific aims are proposed to determine this hypothesis. In the first aim, we plan to use mouse GVHD models to identify the phenotypic and functional characteristics of Dll4+DCs and their important roles in mediating GVHD.
The second aim i s designed to define the mechanisms that regulate the development of Dll4+DCs. We will examine whether and how STAT3 interacts with NF-?B signaling to control the expression of Dll4 in DCs. Molecular insights into the development of Dll4+DCs may lead to the identification of novel targets for modulating GVH responses.
The final aim will be to establish the beneficial effects of modulating Dll4+DCs on improving GVT in mice of allo-HSCT and leukemia. The goal of this aim is to design a new therapeutic strategy to augment GVT while limiting GVHD. Understanding the role of Dll4+DCs in alloimmunity will lead to the development of novel and clinically relevant approaches to augment antitumor immunity, which could be potentially beneficial to approximately 10,000 new patients who receive allo-HSCT every year. Given the central role of DCs in adaptive immunity, results from these studies may have significant implications in the improvement of tumor immunity and control of other inflammatory disorders such as graft-rejection of transplanted organs and autoimmune diseases in broad context.

Public Health Relevance

Allogeneic hematopoietic stem cell transplantation represents the most striking example that immune cells can destroy tumor cells and cure cancer. New methods to enhance graft-versus-tumor activity without excessive graft-versus-host disease are urgently needed to improve the efficacy of this procedure. Understanding of role of Delta-like ligand 4+ dendritic cells in alloimmunity and tumor immunity will lead to the development of novel and clinically relevant approaches to augment antitumor immunity, which could be potentially beneficial to approximately 10,000 new patients who receive allogeneic bone marrow transplantation every year.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA172106-01
Application #
8416792
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2012-12-15
Project End
2017-11-30
Budget Start
2012-12-15
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$322,663
Indirect Cost
$115,163
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109