The present revision application is based on the original RO1 application entitled Effects of PGE2 on reconstitution of hematopoiesis and immunity after umbilical cord blood transplantation (UCBT) (R01 CA183605-01). During the past 15 months we performed studies to investigate the effects of PGE2 in T cells. Using microarray gene expression analysis we determined that a number of genes were selectively altered by PGE2 in UCB T cells. The most striking effect was detected on the expression of the transcription factor NR4A2. NR4A transcription factors have recently emerged as regulators of metabolic function. Using ChIP-PCR, we found that PGE2-induced NR4A2 could bind on the promoter of carnitine palmitoyltransferase (CPT1A), the rate limiting enzyme of fatty acid transport to the mitochondria, resulting in upregulation of CPT1A and increased rate of fatty acid oxidation (FAO) in T cells. PGE2 also diminished the expression of the glucose transporter Glut 1 and the uptake of glucose and this effect was more prominent in CD8+ T cells. Using antigen-specific mouse CD8+ T cells and a model system of in vitro differentiation of T effector and T memory cells, we found that PGE2 promoted T memory cell differentiation. We also determined that PGE2 treatment of the UCB grafts had a significant clinical impact on pathogen-specific and tumor-specific immunity. Compared to control UCBT recipients, PGE2-UCBT recipients had significantly reduced incidence of EBV and CMV reactivation, and reduced incidence of leukemia relapse. Divergence in the metabolic reprogramming of T cells is critical to effectively imprint distinct T cell fates. It has been shown that metabolic switch to FAO promotes the conversion of CD8+ T effector to long-lived T memory cells. Enforcing FAO in various T cell experimental systems induced increased numbers of memory CD8+ T cells and resulted in the generation of memory precursors, TCM and TSCM cells, which display enhanced anti-tumor function. Taken together our in vitro findings on the effects of PGE2 on T cell metabolic reprogramming and T memory cell development, and our clinical observations of improved immunity in PGE2-UCBT recipients suggest that PGE2 treatment might improve anti-tumor immunity by mediating metabolic reprogramming of tumor-specific T cells. This approach might represent a novel method to generate potent tumor-specific T cells for cell based tumor immunotherapy. To address this hypothesis in this revision application we will pursue the following specific aim to: SA1: Determine the mechanisms of PGE2-mediated metabolic reprogramming and its effects on the generation and function of tumor-specific T cells. A) To determine the effects of PGE2 on the molecular, metabolic and gene expression programs of tumor- specific mouse T cells and on their anti-tumor function in vivo. B) To determine the effects of PGE2 on the molecular and metabolic and functional properties of tumor-specific human T cells.
Our studies will examine a novel immunomodulatory effect that PGE2 has on T cells. We determined that PGE2 induced metabolic reprogramming of human CD8+ T cells. PGE2 treatment of UCB grafts also had a significant clinical impact on tumor-specific immunity in PGE2-UCBT recipients. If PGE2-mediated metabolic reprogramming favors generation of CD8+ memory cells with improved anti-tumor function, this novel approach will have significant implications for harnessing immune memory in the context of tumor-specific immunity and can be used to improve cell based therapies for the treatment of leukemia and solid tumors.
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