Restoring aging T cell function to make them effective at fighting cancer

Aging T cells have been found to be less effective at combating cancer, posing a significant challenge to cancer immunotherapy. Led by Alex C.Y. Chen and Debattama (Deb) Sen, researchers at Mass General Brigham Cancer Institute have identified genes that could serve as prognostic markers and therapeutic targets to restore T cell function in the aged immune system.

The study, published in Cell, employed CRISPR screening in aged tumor-bearing mice to pinpoint regulators of T cell dysfunction. Two genes, dual specificity phosphatase 5 (Dusp5) and zinc finger protein 219 (Zfp219), emerged as crucial players. Dusp5 acts as a brake on ERK signaling pathways, which aid in T cell proliferation. When Dusp5 is removed, ERK signaling becomes more active, allowing T cells to proliferate more effectively.

Conversely, Zfp219 functions as an off switch for genes that produce granzymes, tumor-fighting enzymes. When Zfp219 is knocked out, T cells increase the secretion of granzymes, enhancing their ability to kill tumor cells.

The researchers discovered that older adults have higher levels of ZNF219 in T cells within their tumors, and these elevated levels are linked to poorer responses to immune checkpoint blockade and shorter survival. ZNF219 may thus serve as a new prognostic marker for cancer patients based on their age. Furthermore, blocking ZNF219 activity could potentially improve T cell function and cancer treatment outcomes for older adults.

While directly targeting ZNF219 with drugs may be challenging, alternative strategies such as genetically modifying a patient's own T cells through CAR-T cell therapy or other engineered T cell treatments could offer a viable path to reduce ZNF219 activity and bolster the body's ability to fight cancer.