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Epigenetic Regulation of T cell Activation and Immunotherapy

The Johns Hopkins University School of Medicine
Brian Ladle, MD, PhD
Grant Type: 
Young Investigator Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

One reason cancer cells grow uncontrollably is because they turn off genetic brakes on growth using a process called DNA methylation. Drugs that block DNA methylation appear to stop cancer from growing and make it more sensitive to other treatments. However, little is known about the impact of these drugs on the normal immune system.

The enzymes that cause DNA methylation are expressed at high levels in T cells of the immune system after activation but only a few genes they turn off are known. We have shown that blocking these enzymes in T cells changes the type of immune response in a way that may help the immune system to destroy cancer cells.

Project Goal
My project seeks to understand:
1) How DNA methylation limits T cell killing of tumor cells, and
2) How blocking DNA methylation can improve cancer vaccines to treat pediatric cancers.

We predict blocking a key DNA methylation enzyme will improve vaccine responses in mice and allow us to identify new genes that are turned off in T cells by DNA methylation. We will use this knowledge to improve the effect of cancer-specific tumor vaccines by giving them in combination with drugs that block DNA methylation.

Project Update (March 2017)

Our research tries to develop treatments for cancer that will activate your immune system – specifically T cells – to seek out and destroy cancer, no matter where it is in the body or when it might come back. Cancers find ways to shut off the immune system and allow tumor growth and spread. We’re trying to understand how to overcome these suppressive signals and generate strong anti-cancer immune responses. We have discovered that the protein DNMT3a found in your immune cells controls how your immune system can generate a memory response to an infection or tumor. Using mouse models, we are now trying to improve the effectiveness of cancer vaccines combining them with drugs that inhibit DNMT3a.