Abstract
Abstract
Background
T-cell exhaustion is a hallmark of immunological failure to control chronic viral infection and cancer. Blocking inhibitory receptors such as programmed death-1 (PD-1) can re-invigorate exhausted T cells (TEX) in animal models of chronic viral infection and in cancer patients. However, many patients still fail to achieve durable tumor control when treated clinically with checkpoint inhibitors. Thus, a deeper understanding of other molecular pathways and epigenetic mechanisms underlying reversal of T-cell exhaustion is needed. Human chronic infection by HCV represents a unique model, where treatment with novel DAAs leads to complete virological cure even following years of chronic infection. Whether TEXin these cured subjects convert to functional and durable memory cells remains unknown.
Aims
To investigate whether TEX become “reprogrammed” into more functional effector or memory T cells (TMEM) following cure of chronic disease by non-immunological treatment.
Methods
In order to study the reprogramming of TEX following cure of chronic viral infection, we will examine virus-specific T cells from chronic HCV patients cured by DAA treatment and from mice cured of chronic lymphocytic choriomeningitis virus (LCMV). We will determine the cellular, transcriptional, and epigenetic profiles of these cells. And using our well-defined tractable mouse model we will dissect the molecular pathways and mechanisms underlying the changes in TEX following the elimination of continuous exposure to viral antigens. These mechanistic discoveries and predictions from the LCMV model would then be extended and tested in the HCV model in humans.
Results
Our data indicate that some markers of exhaustion (including PD-1) are downregulated, while some markers of TMEM may be recovered upon cure of infection. Nevertheless, other aspects of TEX biology do not appear to be corrected simply by eliminating exposure to chronic infection. Ongoing studies are investigating whether these changes are linked to selective recovery of a specific subset of TEX, and whether improvements are accompanied by changes in the epigenetic landscape of these previously-exhausted T cells.
Conclusions
We expect these studies to enhance our understanding of the epigenetic signatures and the immunological mechanisms of recovery of TEX. These studies should also identify candidate transcriptional circuits differentially regulated in readily-recovered T cells that could represent novel therapeutic targets for reversal of immune-exhaustion.
Funding Agencies
To EJW, NIH grants. To MSA, fellowships from Cancer Research Institute (CRI), FRQS and CanHepC.