In people with chronic infections or cancer, disease-fighting T cells tend to behave like an overworked militia — wheezing, ill-prepared, tentative, in a state of “exhaustion” that allows disease to persist. In a paper posted online by the journal science researchers at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center report that, in mice with chronic viral infection, exhausted T cells are controlled by a fundamentally different set of molecular circuits than T cells effectively battling infections or cancer.

An accompanying study, led by researchers at the University of Pennsylvania and co-authored by Dana-Farber scientists, reports that these differences in circuitry remain largely unchanged by a type of cancer immunotherapy known as checkpoint inhibition, potentially closing off one avenue of improving this technique.
The studies bring renewed focus to the epigenetics of T cells — the multilayered system of molecular switches, accelerators, and throttles that controls the activity of genes. Scientists have known for years that the pattern of genes is different in exhausted T cells than in functional T cells that are fully engaged in fighting disease, but the actual extent of these differences has been uncertain.

One difference that is clear is that exhausted T cells express the programmed cell death protein-1 (PD-1), which commands them not to attack normal, healthy cells, but can also prevent them from striking at cancerous or chronically infected cells. Blocking PD-1 with checkpoint-inhibiting drugs — and thereby restoring the cancer-killing zeal of T cells — has become one of the most successful new approaches to cancer treatment in nearly a decade. However, it has shown effectiveness in only about a quarter of cases.

The work described in the new study suggests that while T cells are being engineered to produce the sensor, they could also be retooled to delete the genetic wiring that causes them to express excessive levels of PD-1 or other exhaustion genes. The resulting CAR T cells not only would be better at stalking cancer, but also more aggressive about attacking it.

In the companion paper, researchers explored whether blocking the PD-1 checkpoint rewired exhausted T cells to make them, from an epigenetic standpoint, more like functional T cells. Using chronically infected mouse models, as in the first study, the investigators found that while such gain of function does occur briefly, the epigenetic switches from its previous, exhausted state remain largely unchanged.

“This suggests that the benefits achieved by checkpoint blockade result from a transient revving up of exhausted T cells, not a permanent reshaping of their state,” Haining said.

The findings of the two studies point to the need for a comprehensive atlas of the regulatory regions that are active in exhausted and functional T cells, he continued. Such a guide would provide targets for rewiring T cells with genetic engineering or epigenetic drugs to make them more effective cancer killers.

DRAFT BY: Juilee Mhatre

SOURCE: Science tech daily


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