Reducing the T Cell Exhaustion Caused by Cancer
Cancers employ a range of mechanisms to subvert and suppress the activities of immune cells attempting to destroy cancerous cells. One issue that appears inherent to T cells of the adaptive immune system, however, is the exhaustion that sets in following repeated exposure to molecules present on cancerous cells or in the tumor environment that trigger T cell receptors. This is how T cells identify targets. Individual T cells are initially effective at killing cancerous cells after T cell receptor interactions, but then become increasingly less effective over time. Can this be prevented? Potentially yes, but the processes involved are not simple, as researchers here explain.
The T cells found in the human immune system are some of the front-line soldiers in recognizing, attacking, and directing the fight against foreign cells and molecules. They recognize their opponents-from pathogens to cancers-through unique receptors on their surfaces. When a molecule binds to one of these T cell receptors, it activates the T cell, which begins producing a variety of immune molecules. Scientists have long known, however, that this response diminishes over time. When a T cell receptor is activated continuously for weeks or months, the cell gradually produces fewer immune molecules and becomes less effective at destroying a cancer or pathogen.
Researchers long thought that T cell exhaustion might be driven by just a few genes that ended up permanently switched on or off after chronic receptor activation. But in recent years, studies on exhausted T cells began to hint that the cells undergo more major rewiring, with thousands of genes turned on or off. The genes found to be linked to T cell exhaustion helped support this idea; the most critical genes were epigenetic regulators, which remodel the physical structure of DNA to turn on or off hundreds of genes at once. These findings help explain how completely different an exhausted T cell is from other functional T cell states.
The researchers carried out detailed analyses of the epigenetic regulators identified in their screen to understand how they interacted with each other, and homed in on a few particularly important genes. Then, they used CRISPR/Cas9 gene editing to further study the effects of blocking individual genes in T cells that were delivered into living mice. They showed that in mice with tumors, blocking the gene Arid1a led to higher levels of T cells and smaller tumors after just 15 days. Moreover, at a molecular level, the T cells from those mice more closely resembled healthy, persistent immune cells than exhausted, less active T cells.
Link: https://gladstone.org/news/scientists-prevent-exhaustion-cancer-fighting-t-cells