Photo by Rob Press
Manipulating metabolic events might reinvigorate exhausted T cells and complement the effects of checkpoint inhibitors in the treatment of cancers, according to research published in Immunity.
When T cells are activated because of a tumor or microbe, they transition from a catabolic existence of slow metabolic burn to an anabolic one in which the body revs up to generate chemical intermediates to build new cells.
However, T cells are hard-wired to stop the anabolic mode at a certain point because functioning at that level is unsustainable.
PD-1, a cell surface receptor and target of checkpoint inhibitors, tells T cells to turn off the anabolic pathway, but other molecular signals attempt to keep this pathway turned on because growing tumors or chronic infection are still present.
This results in “metabolically confused” T cells, said study author E. John Wherry, PhD, of the University of Pennsylvania School of Medicine in Philadelphia.
To study this, Dr Wherry and his colleagues induced infection in mice using 2 different strains of the lymphocytic choriomeningitis virus, a model system for exploring T-cell biology.
“We found that, as early as the first week of a chronic viral infection, even before severe T-cell dysfunction becomes established, virus-specific T cells are already unable to match the bioenergetic demands of T cells generated during the height of fighting a well-contained viral infection in a mouse model,” Dr Wherry said.
In other words, these experiments revealed when PD-1 turns off the anabolic metabolism signal, and it’s earlier than previously thought.
The researchers said this finding is important because it identifies the altered metabolism as a distinct point in the development of exhausted T cells, rather than as a later consequence of exhausted T cells.
This research also revealed PD-1’s role as the metabolic switch in shutting down anabolic pathways and characterized downstream metabolic regulator targets of PD-1.
For example, restriction of glucose uptake and utilization, despite the upregulation of multiple backup metabolic pathways, was one metabolic defect in the exhausted T cells. PD-1 partially controls the development of this early defect in using glucose as a fuel, as well as the size and quality of mitochondria.
A second pathway repressed by PD-1 involved PGC-1α, a protein that regulates genes involved in metabolism. Correcting this PD-1-induced defect by overexpressing PGC-1α improved exhausted T-cell bioenergetics.
The researchers said these results have implications for therapeutic strategies aimed at the reinvigoration of exhausted T cells in chronic infections and cancer. And targeting exhausted T-cell metabolism could complement the effects of blocking PD-1 and other checkpoints.
