In a study published in Nature Communications, the research team reported that that a protein called DUSP4 sharpens the lethality of some T cells that can directly kill cancer cells
Researchers from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) have identified a protein that could help keep these cancer-fighting immune cells active and potentially provide a new way to strengthen engineered T-cell therapies against colorectal cancer.
In a study published in Nature Communications, the research team led by Associate Professor Zhang Yongliang, Department of Microbiology and Immunology, and Immunology Translational Research Programme (TRP), NUS Medicine, found that a protein called dual-specificity phosphatase 4 (DUSP4) helps CD8+ T cells, a type of immune cell that can directly kill cancer cells, maintain their anti-tumour function.
When DUSP4 was absent, these cells became less effective and showed more signs of exhaustion, while laboratory models developed a greater colorectal tumour burden.
When DUSP4 was absent, these cells became less effective and showed more signs of exhaustion, while laboratory models developed a greater colorectal tumour burden.
The researchers also explored whether DUSP4 could improve CAR-T therapy, in which T cells are genetically engineered to recognise cancer cells. In laboratory models, increasing DUSP4 activity helped CAR-T cells multiply more readily and kill colorectal cancer cells more effectively. This is important because CD8+ T cells can become “exhausted” within tumours, gradually losing their ability to multiply and attack cancer—a major challenge for immunotherapies targeting solid tumours.
Prof Zhang said, “CD8+ T cells are among the immune system’s main weapons against cancer, but prolonged exposure to tumours can gradually weaken their ability to function. Our findings suggest that DUSP4 helps keep these cells in a state where they can continue to multiply and attack cancer cells effectively.”
The researchers next explored whether this knowledge could be used to improve CAR-T therapy, in which a patient’s T cells are genetically engineered to recognise cancer cells. Using CRISPR activation, or CRISPRa, the team increased DUSP4 activity in human CAR-T cells. Compared with standard CAR-T cells, the DUSP4-enhanced cells multiplied more readily and showed greater cancer-killing activity against colorectal cancer cells in laboratory experiments. In laboratory models, treatment with these cells also resulted in smaller and lighter tumours than treatment with standard CAR-T cells.
