Current checkpoint immunotherapies work by re-activating dysfunctional T cells and improving their ability to kill cancer cells. Although the majority of patients initially respond to therapy, most eventually relapse. One of the current challenges in the field is to understand the behavior of these T cells after checkpoint immunotherapy. This knowledge will be critical to improving long-term clinical remission. To address that challenge, Dr. Josephine Giles is looking at whether permanent alterations occur in T cells as reflected by changes in the 3D structure of their DNA, which dictates which of their genes are turned on or off. By analyzing immune cells from melanoma patients both before and after immunotherapy, and then comparing their profiles to normal functional T cells, Dr. Giles aims to determine the extent to which these cells are re-activated. Additionally, she plans to probe the roles of various genes and their regulatory regions that are predicted to influence immune cell dysfunction as well as successful reinvigoration after treatment. Overall, these results should significantly enhance our understanding of how cancer-induced immune dysfunction is encoded in DNA’s structure as well as provide new insights and targets that can be used to improve outcomes for patients in the clinic.
Projects and Grants
Defining the transcriptomic and epigenetic reprogramming of human tumor-infiltrating CD8 T cells after PD-1 blockade
University of Pennsylvania | All Cancers | 2018 | E. John Wherry, Ph.D.
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