It's a good news, bad news scenario for exhausted T cells in chronic infections.
Multiple groups of investigators reported in the July 26, 2021, online issue of Nature Immunology that even after a chronic hepatitis C virus (HCV) infection was cured, T cells that had become dysfunctional during the infection retained epigenetic "scars" that prevented them from becoming fully functional memory T cells.
Those findings were "disappointing," Debattama Sen told BioWorld Science. "If chronic stimulation drives exhaustion, we were really hoping that if you take the chronic stimulation away, then the exhaustion would also go away."
On the other hand, exhaustion appeared to be driven not by the inflammatory milieu that was a consequence of chronic HCV infections, but by antigen-driven signaling. And because of that, the exhaustion was specific to T cells that recognized viral antigens.
Sen said the comparison between the T cells was the biggest surprise of the work she and her colleagues reported in Nature Immunology.
"My expectation was that any T-cell population is going to look different" in a healthy person versus one with a chronic infection. But "even in a chronically infected patient most T cells are perfectly healthy."
T cells are critical both for the immune system's ability to control cancer, and to fight off infections.
But "a major challenge has been for them that in chronic settings like viral infections or cancer, where I would say the clinical need is, they become dysfunctional," Sen explained.
Exhaustion is also an issue for CAR T cells, which can become ineffective over time, driving relapse.
And exhaustion is one issue that has hampered the success of CAR T cells in solid tumors. Sen and her team are ultimately interested in understanding how to fight exhaustion in cancer. In their work, however, they used HCV infection as a model.
With the advent of curative therapies for hepatitis C, "in HCV we have this unique opportunity to take patients that have had chronic infection for years, and cure them," Sen explained.
Sen's team, as well as groups led by E. John Wherry at the University of Pennsylvania and George Lauer at Massachusetts General Hospital, demonstrated that even after such a cure, though, CD8-expressing "killer" T cells had lasting battle scars, in the form of epigenetic changes that, among other things, prevented them from becoming full-fledged memory T cells.
They also identified specific regulatory regions that remained impaired due to such epigenetic changes.
Sen and her team want to understand the epigenetic scars in more detail, and see whether the phenomena they have observed in HCV infection are applicable to cancer in general, and CAR T cells more specifically.
It may also be possible to reverse the scarring with gene editing technologies. Aiming gene editing at regulatory regions may be more specific than approaches that target molecules such as checkpoint blockers, because regulatory regions are likely to affect only a subset of cells.
Sen acknowledged that reversing T-cell exhaustion is an approach that would need to be handled with care because given how ubiquitous T-cell exhaustion is, "evolutionarily it probably happened for a reason."
But, she said, cancer typically occurs late in life, when reproduction is long done. And so for most of human evolution, cancer has not been a major selective pressure. As a result, "for tumors, our [natural] set point for turning down that response is not optimal."