New Delhi: A team of researchers from the University of California, Davis, has identified a specific genetic mutation in humans that may increase the risk of cancer and reduce the effectiveness of the immune system in fighting solid tumors. The findings, published in Nature Communications, could lead to more effective treatments for difficult-to-treat cancers.
The study focused on a small genetic difference in an immune system protein called Fas Ligand (FasL), which helps immune cells destroy cancer cells through a process called apoptosis, or programmed cell death. The researchers discovered that humans have a unique mutation in the FasL gene that is not present in non-human primates like chimpanzees.
This mutation involves a single amino acid change—serine replacing proline at position 153—making the human version of FasL more vulnerable to being disabled by plasmin, an enzyme commonly found in aggressive solid tumors such as ovarian, colon, and triple-negative breast cancer.
“The evolutionary mutation in FasL may have contributed to the larger brain size in humans,” said Jogender Tushir-Singh, Associate Professor at UC Davis’ Department of Medical Microbiology and Immunology.
“But in the context of cancer, it was an unfavorable tradeoff because the mutation gives certain tumors a way to disarm parts of our immune system.”
In simple terms, even when human immune cells are activated—including specially engineered CAR-T cells—their ability to kill cancer cells is weakened if the FasL protein is inactivated by the tumor environment. This may explain why immunotherapies like CAR-T are often successful in treating blood cancers but less effective against solid tumors, which tend to rely on plasmin to grow and spread.
Encouragingly, the study also found that blocking plasmin or protecting FasL from cleavage could restore its cancer-fighting ability. This opens up new possibilities for enhancing immunotherapy by combining it with plasmin inhibitors or designing protective antibodies for FasL.
“Humans have a significantly higher rate of cancer than chimpanzees and other primates,” Tushir-Singh noted.
“There’s still a lot we can learn from studying primates to improve how we treat cancer in humans.”
He added that the research marks an important step toward personalizing immunotherapy, especially for patients with plasmin-positive tumors that have so far been hard to treat.