Candidate I am a second year Instructor in the Division of Pediatric Oncology at the Johns Hopkins University School of Medicine. In this proposal I aim to complement ongoing research in immunology with a formal bioinformatics education to permit me to analyze genome-wide patterns of DNA methylation in lymphocytes, in particular in T cells that have been activated by tumor antigen. My immediate goals are to test the hypothesis that DNA methylation and silencing of T cell activation genes contributes to the ineffective immune responses against cancer. My long-term goal is to utilize this proposal to establish an independent line of research that may be translated into clinically relevant immunotherapy for patients in the Division of Pediatric Oncology. Research My prior efforts have identified a critical role for DNA Methyltransferase 3a (DNMT3a) in catalyzing de novo DNA methylation of cytokine genes in T cells following activation. In this proposal I will test the hypothesis that such methylation contributes to ineffective anti-tumor immunity. I will use a robust model of mice whose T cells lack DNMT3a to identify unappreciated targets of DNA methylation by comparing tumor exposed and activated T cells in an genome-wide methylation analysis. I will determine whether lack of such methylation underlies the observed ability of DNMT3a KO T cells to better reject tumors, and I will test whether treatment DNMT inhibitors can achieve a similar effect. Such a finding would identify DNMT inhibition as a novel means of enhancing anti-tumor immunity and potentially lead to more effective cancer vaccine strategies. Environment: My proposal will be carried out under the ongoing mentorship of Dr. Jonathan Powell, a leading researcher in the biology of T cell activation, effector differentiation, and tolerance. He leads a highly productive laboratory and has successfully mentored four graduate students and three postdoctoral fellows. Through collaboration with Dr. Srinivasan Yegnasubramanian, Director of the Next Generation Sequencing Center, I will apply the latest technological advances in next generation sequencing to the measurement of global patterns of genomic DNA methylation. The Center for Biotechnology Education and the Center for Computational Genomics will provide a curriculum for formal education in bioinformatics. These elements combine to provide me with a solid foundation to develop a career as an independent physician-scientist.
Project Narrative We propose that tumors bypass and suppress T cell immune responses by turning off genes within T cells using a process called DNA methylation. This project seeks to identify T cell genes turned off by tumors due to DNA methylation and test whether blocking DNA methylation is able to enhance immune responses against tumors. Identifying a role for DNA methylation in preventing anti-tumor immunity suggests that drugs that block DNA methylation will enhance treatment of cancer with immunotherapy.
|Ladle, Brian H; Li, Kun-Po; Phillips, Maggie J et al. (2016) De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8+ T-cell fate decisions following activation. Proc Natl Acad Sci U S A 113:10631-6|
|Thomas, Rajan M; Gamper, Christopher J; Ladle, Brian H et al. (2012) De novo DNA methylation is required to restrict T helper lineage plasticity. J Biol Chem 287:22900-9|