Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation, an established therapy for patients with hematological malignancies. Current strategies to diminish GVHD include T-cell depletion and immunosuppressive drugs, which are associated with an increased risk of tumor relapse, opportunistic infection, and/or toxicity. Novel approaches acting intrinsically on the immune system are clearly needed. Myeloid-derived suppressor cells (MDSCs) consist of a population of myeloid precursor cells that exhibit potent suppressive activities capable of dampening anti-tumor responses, autoimmunity, and allo-responses in graft-versus-host diseases (GVHD) and organ transplantation. Our preliminary results indicate that MDSCs have several attractive attributes as helper cells to inhibit GVHD without significantly compromising graft-versus-leukemia/lymphoma (GVL) in a murine model, resulting in the establishment of long-term survival. Recently, we also demonstrated that MDSCs acquire M1 or M2 functional macrophage phenotypes through regulation of PIR-B (paired immunoblobulin-like receptor B and human counterpart inhibitory immunoglobulin-like receptors B, LILRBs) signaling, which may facilitate the development of antitumor responses or mediate immune suppression and Treg activation, respectively. The objective of this proposal is to understand the mechanism by which MDSC biological function is regulated and to devise an optimized protocol for directing the functional activities of MDSC toward suppression of GVHD while allowing sufficient GVL activity to eradicate tumors. Based on the results of ou preliminary studies, we hypothesize that: (i) The functional phenotype of MDSC can be modulated by PIR-BL ligation and (ii) The presence of MDSCs with a persistent M2 functional phenotype may be sufficient to prevent GHVD and retain GVL ability.
Three specific aims will be pursued:
Aim 1. Study the regulation of MDSC function and the associated effects on GVHD.
Aim 2. Study the effects of PIR-B ligation on MDSC as related to inhibition of GVHD and the corresponding signaling regulation in an irradiated host.
Aim 3. Study the mechanism and effects of MDSC mediated regulation of GVHD vs. GVL through PIR-B/LILRB engagement in mouse GVHD models and in a human xenograft NSG mouse model. The proposed studies will provide the basis and scientific principles for future clinical translation.

Public Health Relevance

The goal of this project is: 1) to identify the MDSC linage commitment for the effect on GVHD vs. GVL~ 2) the mechanism underlying Using PIRB ligand to control MDSCs differentiation and achieve better therapeutic outcome. The information gained from these studies will provide the basis for the mobilization and modulation of human MDSCs from bone marrow for use in clinical settings.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127483-09
Application #
9235135
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Sommers, Connie L
Project Start
2007-04-01
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
9
Fiscal Year
2017
Total Cost
$307,044
Indirect Cost
$125,897
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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van der Touw, William; Chen, Hui-Ming; Pan, Ping-Ying et al. (2017) LILRB receptor-mediated regulation of myeloid cell maturation and function. Cancer Immunol Immunother 66:1079-1087
Wang, Juan; Peng, Liang; Zhang, Ruihua et al. (2016) 5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation. Oncotarget 7:19312-26
Bronte, Vincenzo; Brandau, Sven; Chen, Shu-Hsia et al. (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150
Chen, Hui-Ming; Ma, Ge; Gildener-Leapman, Neil et al. (2015) Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy. Clin Cancer Res 21:4073-4085
Conde, Patricia; Rodriguez, Mercedes; van der Touw, William et al. (2015) DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance. Immunity 42:1143-58
Eisenstein, Samuel; Chen, Shu-Hsia; Pan, Ping-Ying (2014) Immune cells: more than simple carriers for systemic delivery of oncolytic viruses. Oncolytic Virother 3:83-91
Wang, Ying; Chen, Kun; Wu, Zhiyuan et al. (2014) Immunizations with hepatitis B viral antigens and a TLR7/8 agonist adjuvant induce antigen-specific immune responses in HBV-transgenic mice. Int J Infect Dis 29:31-6
Shen, Jin; Chen, Xiaojuan; Wang, Zhenxing et al. (2014) Downregulation of CD40 expression contributes to the accumulation of myeloid-derived suppressor cells in gastric tumors. Oncol Lett 8:775-780
Eisenstein, Samuel; Coakley, Brian A; Briley-Saebo, Karen et al. (2013) Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy. Cancer Res 73:5003-15

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