Insight on T cell exhaustion may improve immunotherapy treatment outcomes

Model of a T cellHazem Ghoneim, PhD, assistant professor of Microbial Infection and Immunity at The Ohio State University College of Medicine, and Amir Yousif, MS, second-year graduate student in the Molecular, Cellular and Developmental Biology Graduate Program at the Ohio State College of Medicine, are working to improve immunotherapy outcomes by exploring and building on T cell research.

Adaptive immunity, a subset of the immune system, is a powerful community of specialized cells responsible for the body’s efficient, targeted response to infections. One of the specialized cells of this system are killer T cells. These cells’ key role in adaptive immunity is attributed to their highly selective cytotoxic activity that aids in the precise destruction of foreign pathogens or tumor cells. Once this mission is completed, some surviving killer T cells generate long-lived memory cells that provide long-term protection against reinfections. Though T cells are solely designed for such function, research finds that chronic infections and cancer may exhaust these cells, reducing their quality and function.

The regression of T cell integrity results in a less efficient attack on foreign antigens and a loss of their ability to generate functional memory. In a fully exhausted state, T cells exhibit metabolic dysfunction, decreased proliferation and decreased production of cytokines, the chemical messengers that are imperative to the efficacious function of the immune system. Overall, T cell exhaustion inhibits optimal immune response to infections and tumors, complicating immunotherapy treatments for cancer or chronic viral infections. This leaves researchers with the question of whether and how T cell exhaustion can be reversed after chronic stimulation.

Dr. Ghoneim and Yousif’s commentary, recently published in Nature Immunology, lays a stepping stone in the pathway to answering this question. They reviewed four studies that explore the underlying mechanisms and consequences of this phenomenon and appraise chronically stimulated T cells’ potential for functional recovery. Three of the studies in the commentary examined the profiles of hepatitis C virus (HCV)-specific CD8+ T cells taken from chronically infected patients.

“HCV represents the only chronic virus infection with a cure for humans, so this virus was the ideal model for reviewing the condition of T cells following infection removal and antigen clearing,” says Dr. Ghoneim.

The three studies collectively presented interesting findings, learning that exhausted T cells maintain a unique epigenetic signature that’s shared across mice and humans during chronic viral infections. This signature, defined as physical changes in the T cells' chromatin that affect the expression of genes and thus functional identity, introduced a concept known as scarring. Even after the cure of a chronic infection, exhausted T cells retain the epigenetic scars of exhaustion and may pass their flawed characteristics to the next generation of T cells to hinder full functional recovery. One of the three studies featured in Dr. Ghoneim and Yousif’s commentary found specific exhaustion-associated genes and possible regulators to control for these genes.

The fourth study analyzed the transcriptional and epigenetic profiles of T cell populations in mice infected with chronic lymphocytic choriomeningitis virus (LCMV) and assessed the functional capacity and memory potential of recovered T cells following clearance of chronic infection. Similar to the human HCV studies, this study found that the majority of T cell chromatin regions impacted by chronic LCMV were exhausted and scarred. This is exciting information for Dr. Ghoneim and Yousif, as restoring T cell function could lie in epigenetic reprogramming by targeting the upstream regulators of these scarred regions.

“We surmise several alternative explanations to why epigenetic scars restrain the optimal recovery of T cells and memory development following the resolution of chronic infection, despite apparent phenotypic recovery of T cells,” says Dr. Ghoneim. “The influence of epigenetic programming could be more durable from persistent chronic infections rather than acute infection. Another possible explanation is that fully exhausted T cells become antigen-addicted and are lost when antigens disappear.”

Dr. Ghoneim and Yousif’s commentary also explores the possibility that antigen stimulation may not be the sole reason behind T cell exhaustion. Chronic inflammation and tissue microenvironment, or extrinsic signals within tumors, could influence T cell exhaustion and scarring in chronic viral infections and cancers. Dr. Ghoneim finds that these are all interesting avenues to be explored.

"The main take-home message from these studies is that during chronic virus infections, our killer T cells become exhausted,” says Dr. Ghoneim. “Even after clearing the infection, for example after treatment of chronic hepatitis C virus infections in humans, these exhausted T cells remain dysfunctional due to unique epigenetic scars that cannot be repaired during the recovery. Therefore, developing new therapies to target these epigenetic scars is crucial for protecting humans against re-infections or possibly tumor relapse after immunotherapies.”

Building on this understanding, the Ghoneim Lab is conducting research that follows their initiative to “elucidate the molecular mechanisms that regulate killer T cell function and response to immunotherapies during chronic infections or cancer.” They have developed novel in vitro models to study T cell exhaustion, a new approach that has helped them discover new pathways to therapeutically target and epigenetically reprogram exhausted T cells.

The Ghoneim Lab’s research is redefining immunotherapy by improving the clinical interventions used to tackle and prevent the recurrence of chronic infections and cancer.