The favorable outcome of umbilical cord blood transplantation (UCBT) is compromised by prolonged time to engraftment, delayed immunologic reconstitution and late memory T cell skewing. Zebrafish and mouse studies have shown that transient ex vivo prostaglandin E2 (PGE2) exposure increases HSC number, homing and engraftment in vivo. We performed a Phase Ib clinical trial of double UCBT (dUCBT), using one untreated and one ex vivo PGE2-treated UCB unit, to determine safety and engraftment parameters. We demonstrated a significant reduction in the median time to myeloid engraftment compared with historic controls, and PGE2- derived hematopoiesis. We determined, that short exposure to PGE2 induced stabilization of b-catenin in UCB T cells and dendritic cells (DCs). In UCB T cells PGE2 modified the Wnt signaling cascade through EP2/EP4 receptors and cAMP-mediated phosphorylation of Gsk3, resulting in stabilization of ?-catenin and TCF-mediated transcription. PGE2 induced Wnt target genes, including components of the Wnt pathway but also Wnt receptors, suggesting that ex vivo PGE2 treatment primes T cells for Wnt/?-catenin signaling in vivo. Wnt/?-catenin signaling in mice has been demonstrated to promote the generation of highly potent stem cell memory CD8+ T cells. Consistent with our hypothesis, we found that T cells in PGE2-UCBT recipients displayed limited in vivo expansion, increase in CD62+ cell fraction in the CD8+ population and molecular features of central memory-like cells characterized by increased expression of transcription factors TCF7 and EOMES and low levels of KLRG, all of which are regulated by Wnt signaling. Furthermore, compared to control dUCBT recipients, PGE2-UCBT recipients had improved quantitative and qualitative thymic reconstitution as determined by TREC values and by immunoSEQ assay. These patients displayed potent antiviral immunity and reduced incidence of CMV and EBV viremia. These outcomes are of particular importance in allogeneic HSCT and specifically UCBT where delayed immune reconstitution is characterized by late memory T cell skewing and prolonged impairment of thymic function. Our clinical and laboratory findings suggest that the engrafting advantage of PGE2-treated HSC might allow for the use of a single UCB unit in adult patients, and that PGE2 might alter reconstitution of the innate and adaptive immunity by priming immune cells for Wnt mediated signaling in vivo. To these ends we will undertake the following studies to: 1) Determine the clinical outcome of single ex vivo PGE2 incubated UCB unit transplantation. 2) Examine the effect ex vivo PGE2 incubation of the UCB on the differentiation, polarization and function of T cells. 3) Examine the effects of ex vivo PGE2 incubation of the UCB on the molecular and functional properties of DC.

Public Health Relevance

Our proposal will test the hypothesis that PGE2 pre-incubation of the stem cell graft provides a novel approach to accelerate HSC engraftment and to improve immunity by altering the properties and functions of T cells and DC. If these studies are successful, they will have major implications on the outcome of UCBT, in which delayed engraftment and impairment of immunity are serious causes of morbidity and mortality and compromise quality of life.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA183605-01
Application #
8588715
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Merritt, William D
Project Start
2013-07-17
Project End
2018-04-30
Budget Start
2013-07-17
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$573,875
Indirect Cost
$159,983
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Karantanos, Theodoros; Politikos, Ioannis; Boussiotis, Vassiliki A (2017) Advances in the pathophysiology and treatment of relapsed/refractory Hodgkin's lymphoma with an emphasis on targeted therapies and transplantation strategies. Blood Lymphat Cancer 7:37-52
Boussiotis, Vassiliki A (2016) Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N Engl J Med 375:1767-1778
Karantanos, Theodoros; Christofides, Anthos; Bardhan, Kankana et al. (2016) Corrigendum: Regulation of T Cell Differentiation and Function by EZH2. Front Immunol 7:346
Patsoukis, Nikolaos; Bardhan, Kankana; Weaver, Jessica et al. (2016) The role of metabolic reprogramming in T cell fate and function. Curr Trends Immunol 17:1-12
Christofides, Anthos; Karantanos, Theodoros; Bardhan, Kankana et al. (2016) Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2. Oncotarget 7:85624-85640
Herbel, Christoph; Patsoukis, Nikolaos; Bardhan, Kankana et al. (2016) Clinical significance of T cell metabolic reprogramming in cancer. Clin Transl Med 5:29
Bardhan, Kankana; Anagnostou, Theodora; Boussiotis, Vassiliki A (2016) The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation. Front Immunol 7:550
Karantanos, Theodoros; Boussiotis, Vassiliki A (2016) JAK3-mediated phosphorylation of EZH2: a novel mechanism of non-canonical EZH2 activation and oncogenic function. Transl Cancer Res 5:S1208-S1211
Patsoukis, Nikolaos; Bardhan, Kankana; Chatterjee, Pranam et al. (2015) PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 6:6692
Satyanarayana, Gowri; Hammond, Sarah P; Broge Jr, Thomas A et al. (2015) BK polyomavirus reactivation after reduced-intensity double umbilical cord blood cell transplantation. Transpl Immunol 32:116-20

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