Regulatory T cells (Tregs) are characterized by expression of master regulator, Foxp3, and their ability to limit autoimmunity and maintain peripheral tolerance. However, these cells also play a deleterious role in suppressing the anti-tumor response. Our lab found that deletion of neuropilin-1 (Nrp1) on Tregs results in decreased suppression of the anti-tumor response without compromising peripheral tolerance. We also found that these cells change their phenotype, such as secretion of IFN? and loss of suppressive capability, but maintain Foxp3 expression, which we coined as Treg fragility. We have also shown that IFN?-mediated Treg fragility is required for a productive immunotherapeutic response to anti-PD1 immune checkpoint blockade in mice. Interestingly, we found that IFN? causes DNA methylation of an enhancer element that exists in the Foxp3 locus, the conserved non-coding sequence 2, or CNS2 in vitro. We do not yet know if IFN? causes re-methylation of other Treg-specific de-methylated regions (TSDRs). It is possible that this re-methylation could contribute to Treg fragility. This research proposes to elucidate how IFN? contributes to Treg fragility in two specific aims. First, it would be of interest to understand how IFN?-mediated DNA re-methylation occurs. We will examine if downstream modulator STAT1 can modulate levels of the DNA methyltransferase enzymes (DNMT1, DNMT3a, and DNMT3b) as well as differential binding to TSDR loci. Next, we will elucidate if IFN? causes re-methylation of TSDR loci in vivo after anti-PD1 therapy. Moreover, we will elucidate if CD8 T cells are the source of the IFN? after treatment. These proposed studies will give insight on the mechanisms of Treg fragility.

Public Health Relevance

Regulatory T cells are a critical component of the immune system; they play an important role in limiting autoimmunity. Unfortunately these cells can prevent an immune-mediated attack against tumors. This project strives to understand how these cells can become dysfunctional in the tumor and how this is involved in immunotherapeutic response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA236337-02
Application #
9969037
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Korczak, Jeannette F
Project Start
2019-07-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260