New insights into T-cell exhaustion could improve cancer immunotherapies

Specially engineered immune cells called CAR T cells have proven themselves to be a powerful weapon against blood cancers, but against solid tumors they are much less effective, due in part to a process called T-cell exhaustion. Now, researchers at Penn Medicine have illuminated key molecular details of this exhaustion process that point to a specific strategy for overcoming it.

Gloved hands holding a pipette over a lab petri dish.

In the study, published in Cell, the researchers developed a lab dish model that allowed them to comprehensively study the exhaustion process in chimeric antigen receptor (CAR) T cells designed to attack pancreatic tumors. They observed that the T-cell exhaustion process in the model closely resembles that seen in patients’ T cells. The model also reveals new facets of the exhaustion process, including the role of two genetic regulators of exhaustion, ID3 and SOX4, whose silencing allowed CAR T cells to retain much of their effectiveness against the tumor cells.

“This brings us a step closer to next-generation CAR T cell therapies that will be much more effective against solid cancers,” says co-senior author Carl June, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine and director of the Center for Cellular Immunotherapies at Penn’s Abramson Cancer Center.

The other co-senior author of the study is Shelley L. Berger, the Daniel S. Och University Professor in the Department of Cell and Developmental Biology at Penn.

This story is by Caren Begun. Read more at Penn Medicine News.