Discovering how T cell “exhaustion” is triggered could energize cancer immunotherapy

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Ben Youngblood, PhD, right, and Yiping Fan, PhD, found that a gene, Tox, drives T cell exhaustion. This is important because exhaustion inhibits the T cell’s ability to fight disease.

Immunotherapy for cancer has become a highly promising approach to treatment, in which the patient’s own immune cells are activated to attack cancers. Among these promising anti-cancer weapons are cytotoxic T cells. However, a major barrier limiting the efficacy of current treatments is that T cells develop “exhaustion,” reducing their ability to attack cancer cells. As a result, patients treated with immunotherapies against cancers are often non-responsive or suffer a relapse.

Exhaustion is also a process that weakens the cell’s ability to battle such infections as hepatitis C and HIV. Once turned off, the cells seem to reach a point of no return, so understanding how the cells get to that point, and how to prevent it, is critical.

Working with an international team of scientists, my laboratory has made a major step in understanding how this exhaustion is triggered. In a paper published online in the journal , we report discovering that a gene called Tox is a major activator of the genetic machinery of the exhaustion program. The finding offers a prospect of diagnostic tests that enable oncologists to assess whether the T cells to be used in therapy have become exhausted. It is our hope that further basic research also will reveal techniques to treat the cells to prevent exhaustion in the first place.

We have been fortunate in our studies of exhaustion to have an ideal virus that triggers exhaustion in the T cells of its host. Lymphocytic choriomeningitis virus naturally infects mice, and there are two closely related strains that cause either an acute or chronic infection. In the acute strain, the T cells of the mice are exposed to the immune-triggering viral proteins, called antigens, such that they would not develop exhaustion. But in the chronic infection, the T cells are exposed to the same antigen for a long duration, causing them to become exhausted.

By comparing the genes activated in T cell responses to these two strains, we could pinpoint those genes specifically switched on in the kind of chronic infection that results in exhaustion. That comparison revealed the Tox gene as a primary activator, called a transcription factor, of the exhaustion program. We discovered some important aspects of Tox’s function when we knocked it out in the T cells. In this case, the T cell population crashed after a certain amount of time of chronic stimulation.

These experiments revealed that Tox has an unexpected dual function, both producing exhaustion and supporting the long-term survival of the T cells. These functions have an important protective role in the immune system, since a continuing potent response is toxic to the host, in this case mice.

We also conducted experiments in which we essentially dialed-up, or “over-expressed,” Tox in human and mouse T cells. Those experiments showed a heightened exhaustion, supporting Tox’s role in driving the process.

Our studies also revealed that Tox regulates the T cells’ “epigenetic” machinery that remodels the cells to produce exhaustion. Epigenetic machinery consists of molecular switches that turn genes on or off to control the cell. While the genes in the cell’s genome are like data stored on a computer disk, the epigenome is like a set of computer programs that control how that data are read. This finding follows earlier studies in our laboratory that revealed this epigenetic remodeling and how it is passed on to succeeding generations of T cells. In our future studies, we plan to explore the details of how Tox regulates this remodeling.

Given that T cell persistence is strongly correlated with the clinical outcome of existing T cell therapies, we believe that our work T cell has the potential to greatly improve such therapies for the treatment of cancer and viral infections.

About the author

Ben Youngblood, PhD, is an assistant faculty member of the Immunology Department at St. Jude Children’s Research Hospital. View full bio.

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