Researchers Say Cancer Immunotherapy Could Get a Boost from Reinvigorating Extremely Exhausted T Cells

The thinking used to be that when T cells get exhausted to a certain degree they become practically useless and nothing can be done to salvage them. But new research suggests that even the most exhausted T cells can be revived.

T Cell

T-cell exhaustion is a common occurrence in cancer. T cells can become too exhausted from fighting tumor cells. Progenitor-like cells differentiate into poorly-working, terminally-exhausted T cells over time. The process is thought virtually irreversible once it gets to the advanced stage.

Existing immunotherapies for cancer can reverse exhaustion in the early phase of progenitor cells. However, T cells that are terminally exhausted do not usually respond to these therapies and, so, seemingly become useless for fighting tumors.

This new study, led by the University of Pittsburgh and University of Pittsburgh scientists, raises hope of totally exhausted T cells being brought back into action against cancer cells.

“People think about terminally exhausted T cells as a lost cause, that there’s no coming back from this state,” said Amanda Poholek, Ph.D., co-senior study author and the Health Sciences Sequencing Core director at UPMC Children’s Hospital of Pittsburgh. “But given the right circumstances – the T cell version of rest – we show that they can come back.”

The research, published in the journal Science Immunology, could aid in making immunotherapy more effective against cancer cells.

Studying exhausted T cells

Researchers in this study wanted to probe why T cells fail with a view to making immunotherapy more helpful. They, therefore, carried out in-depth analyses of both early and terminally-exhausted T cells in mice that have aggressive melanoma. Profiling of the cells’ epigenome, which contains chemical compounds that attach to DNA and regulate gene expression, was carried out.

The team observed that significant DNA sections had an open structure, which implies a potential for active gene expression. Genes were switched off in those areas, however, indicating that something was impeding gene expression there.

T cells depend on two switches – T cell receptors and a co-stimulatory signal – to be completely activated. Researchers found that insufficient co-stimulation was the problem of terminally-exhausted T cells in this case.

The team, therefore, introduced an antibody that binds to 4-1BB, which is a co-stimulatory receptor. As a result, gene expression improved and the activity of T cells was improved.

“We expected to find exhausted T cells with epigenomes damaged beyond repair, that they were goners,” Poholek said. “So, we were really surprised to find that these cells had the potential for recovery.”

New treatment approaches

Another important finding had to do with hypoxia or low oxygen levels. This is a common occurrence in the tumor microenvironment, as per researchers.

Poholek and her colleagues found that hypoxia played a role in poor gene expression observed in terminally-exhausted T cells. However, these cells differentiated into a better functional state after the scientists reprogrammed them to be hypoxia-resistant.

“Exhausted T cells have what it takes to be functional, but the tumor environment is set up for them to fail,” noted Greg Delgoffe, Ph.D.

The co-senior study author added that the full potential of exhausted T cells can be restored by bringing back oxygen or enhancing co-stimulation. These may help cancer patients to enjoy the benefits of a healthy, well-functioning immune system.

Researchers pointed out that new approaches for reinvigorating exhausted T cells to improve immunotherapy could include the use of hypoxia-targeted drugs. Also, drugs that target co-stimulation pathways may be used or scientists may engineer exhaustion-resistant CAR-T cells.