5 days ago
Evolution: Single Mutation May Explain Humans' Higher Cancer Risk
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A newly discovered genetic mutation unique to humans may help explain why we are significantly more vulnerable to cancer than our closest evolutionary relatives.
Researchers at the University of California, Davis, identified a single amino acid change in a key immune system protein—dubbed "Fas Ligand" (FasL)—that appears to give solid tumors in humans a biological loophole, allowing them to evade immune attack.
The same vulnerability is not present in chimpanzees or other non-human primates, the team report.
"The evolutionary mutation in FasL may have contributed to the larger brain size in humans," said lead author Jogender Tushir-Singh, an associate professor of medical microbiology and immunology at UC Davis.
"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."
3d rendering DNA and flying molecule cells on microscope background, Depth Of Field.
3d rendering DNA and flying molecule cells on microscope background, Depth Of Field.
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Fas Ligand plays a critical role in the immune system's ability to kill cancer cells. Found on the surface of immune cells—including the CAR-T cells used in cutting-edge cancer therapies—FasL triggers a process known as apoptosis, or programmed cell death, in target cells.
The team's investigation reveals that in humans, a single amino acid substitution—from proline to serine at position 153—renders FasL vulnerable to plasmin, an enzyme frequently elevated in aggressive solid tumors like ovarian, colon and triple-negative breast cancers.
When plasmin cleaves FasL, it effectively disarms one of the immune system's key cancer-fighting tools, allowing tumors to grow and spread despite an active immune response.
This mechanism may help explain why immunotherapies like CAR-T cells, which have revolutionized treatment for blood cancers, often struggle to achieve similar success with solid tumors.
Solid tumors create a hostile microenvironment that actively neutralizes FasL using plasmin, the researchers explained. In blood cancers, where plasmin isn't a major factor, immune cells retain more of their killing power.
The team also found that blocking plasmin or modifying FasL to resist cleavage can restore its tumor-killing ability, potentially improving the effectiveness of immunotherapy for solid tumors.
These findings open up new possibilities for enhancing immune-based treatments using plasmin inhibitors or engineered antibodies that shield FasL from degradation.
This could help us overcome one of the key reasons why immune therapies work well in leukemia or lymphoma but have limited success in solid tumors.
While the mutation in FasL may have weakened immune defenses against cancer, the researchers speculate that it may also have been tied to benefits during human evolution—possibly linked to the development of a larger brain.
Such evolutionary tradeoffs, the study suggests, might help explain why cancer rates are significantly higher in humans compared to chimpanzees, despite our shared genetic ancestry.
"There is a lot that we do not know and can still learn from primates and apply to improve human cancer immunotherapies," said Tushir-Singh. "Regardless, this is a major step toward personalizing and enhancing immunotherapy for the plasmin-positive cancers that have been difficult to treat."
Researchers are now exploring clinical strategies to apply these findings. Trials investigating the use of plasmin inhibitors in combination with CAR-T or T-cell therapies for solid tumors may be on the horizon.
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