Study suggests way to re-energise tired T cells when treating cancer

A new study by researchers at The Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James) suggests a way to re-energize critical killer immune cells that have become exhausted when fighting cancer or chronic viral infections.

A recent study from the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James) of The Ohio State University Comprehensive Cancer Center (OSUCCC) suggests a method to reactivate vital killer immune cells that have worn out while battling cancer or persistent viral infections. Immune cells called CD8 T cells are critically important in the immune system's efforts to eliminate cancer cells and virally infected cells from the body. These cells are also key players in immune therapies called immune checkpoint blockade and CAR T-cell therapy.

For this animal and cell study, researchers first developed a new model system to study human CD8 T-cell dysfunction and whether the dysfunction can be reversed. The work revealed that chronic signalling by transforming growth factor beta 1 (TGFb1) accelerates the killer cells' loss of function. It also showed that boosting the activity of a cytokine called bone morphogenetic protein 4 (BMP4) while blocking TGFb1 could preserve the function of chronically stimulated human CD8 T cells. This also improved responses in animal models to tumours and to a chronic viral infections.

The researchers report their findings in the journal Nature Immunology. "When killer T cells become severely dysfunctional, they are unable to effectively clear cancer or viral infections from the body, and they do not respond well to immunotherapies," said principal investigator Hazem Ghoneim, assistant professor in the Department of Microbial Infection and Immunity.

"We found that rebalancing TGFb1 and BMP signalling can unleash these dysfunctional T cells and enhance their response to T cell-based immunotherapies and other immune checkpoint therapies," said Ghoneim, who is also a member of OSUCCC -- James Cancer Biology Research Program. "This novel strategy could potentially improve the effectiveness of these therapies and help to clear chronic infections or tumours more effectively," he added.

Ghoneim and his colleagues reasoned that cues in the tumour microenvironment likely triggered the shift of T cells to a pathway leading to dysfunction. They also reasoned that identifying the key signals involved in that shift would reveal new targets that could improve the effectiveness of T-cell immune therapies. Constant exposure to cancer-cell antigens in the tumour microenvironment causes killer T cells to show signs of mild burnout and to become mildly dysfunctional. The researchers found that these mildly dysfunctional T cells are driven to a state of profound dysfunction by chronic exposure to TGFB1 that remains stable even after resting the cells.

They also found that the cytokine BMP4 limits exhaustion and improves the survival of chronically stimulated CD8 T cells. The researchers then used animal models to show that adjusting the balance of TGFb1 and BMP signalling could:

A. Maintain the tumour-killing ability of human CD8 T cells;B. Boost exhausted T-cell responses to an immune checkpoint blockade therapy; andC. Control a lifelong chronic lymphocytic choriomeningitis viral infection. "Our findings," Ghoneim said, "indicate that relative levels of TGF beta and bone morphogenetic protein in a tumour microenvironment strongly influence the function of chronically stimulated CD8 T cells, revealing a potential new strategy to epigenetically reprogram dysfunctional T cells during immune checkpoint blockade therapy." (ANI)

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