CRISPR screening identified Dusp5 and Zfp219 as genes that impair tumor control by aged T-cells
CRISPR screening identified Dusp5 and Zfp219 as genes that impair tumor control by aged T-cells
On July 29, Cell published a study of the age-related decline in antitumor immunity. The authors knocked out genes in young CD8+ T-cells, transferred the cells into tumor-bearing mice, and compared young animals with 68-week-old mice. Dusp5 and Zfp219 contributed to different defects. Dusp5 limited cell proliferation, while Zfp219 impaired the cells’ ability to kill.
CD8+ T-cells recognize and destroy dangerous cells. Tumors in aged animals contain few of these T-cells, and some of the remaining cells produce fewer granzymes, the proteins immune cells use to destroy their targets. These defects require different immunotherapeutic approaches. One must increase T-cell numbers, while the other must restore their ability to attack.
The authors tested this with a CRISPR screen. They knocked out regulatory genes in T-cells one at a time, then examined which cells remained in the tumors and nearby lymph nodes of aged and young mice after 15 days. The screen yielded eight candidates. Dusp5 and Zfp219 were selected for detailed testing.
Dusp5 limits T-cell expansion. This gene encodes a protein that dampens the ERK signaling pathway. Deleting Dusp5 strengthened ERK-driven proliferation, which increased the number of T-cells in the tumor.
Zfp219 suppresses the target-killing program. Deleting Zfp219 in T-cells from aged mice made DNA regions near the granzyme genes Gzma and Gzmb more accessible. The cells resumed producing granzymes and more often entered a state in which they could kill tumor cells.
In an experiment in aged mice, deleting Zfp219 together with treatment using a PD-1 antibody eliminated the tumor in three of eight animals. When tumor cells were introduced again, these mice maintained control of the tumor.
The authors found a similar signal in older patients. Tumor-infiltrating CD8+ T-cells had higher levels of ZNF219, the human counterpart of Zfp219, and higher levels were associated with poorer survival after PD-1 blockade therapy. The screen identified two distinct intervention points for the age-related decline in immunity. Targeting Dusp5 helps T-cells proliferate, while targeting Zfp219 restores their ability to kill tumor cells.