Human Evolution May Have Left Us More Vulnerable to Cancer

A tiny genetic change that helped give humans their large brains may have simultaneously made us more susceptible to cancer than our closest primate relatives, according to new research from UC Davis Comprehensive Cancer Center.

The study, published in Nature Communications, reveals how a single amino acid substitution in an immune protein called Fas Ligand makes human cancer-fighting cells less effective against solid tumors compared to chimpanzees and other non-human primates.

The Evolutionary Trade-off

Scientists discovered that humans carry a unique mutation where the amino acid serine replaces proline at position 153 in the Fas Ligand protein. This seemingly minor change makes the protein vulnerable to being disabled by plasmin, an enzyme that tumors use to spread throughout the body.

“The evolutionary mutation in FasL may have contributed to the larger brain size in humans,” said Jogender Tushir-Singh, the study’s senior author and associate professor in the 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.”

The research suggests this genetic change helped neural development during human evolution but came with an unexpected cost: increased cancer vulnerability in modern humans.

How Tumors Exploit This Weakness

Fas Ligand serves as a crucial weapon for immune cells, triggering programmed cell death in cancer cells through a process called apoptosis. However, the human version of this protein contains a structural weakness that aggressive tumors can exploit.

In cancers like triple-negative breast cancer, colon cancer, and ovarian cancer, elevated levels of plasmin enzyme can effectively neutralize human Fas Ligand before it kills tumor cells. This mechanism helps explain why certain immunotherapies work well against blood cancers but often struggle with solid tumors.

The researchers found that:

• Human Fas Ligand is highly susceptible to plasmin cleavage
• Chimpanzee and rhesus monkey versions resist this degradation
• Tumors with high plasmin levels show greater resistance to treatment
• Blocking plasmin can restore the cancer-killing power of human immune cells

Clinical Implications

The discovery offers new strategies for improving cancer treatment. By combining current immunotherapies with plasmin inhibitors or specially designed antibodies that protect Fas Ligand, researchers may be able to enhance immune responses against solid tumors.

Testing in patient-derived ovarian cancer cells confirmed that tumors with high plasmin activity were significantly less sensitive to human Fas Ligand compared to the primate versions. Importantly, blocking plasmin activity restored the effectiveness of cancer-killing immune cells.

“Humans have a significantly higher rate of cancer than chimpanzees and other primates,” Tushir-Singh noted. “There is a lot that we do not know and can still learn from primates and apply to improve human cancer immunotherapies.”

The Brain Connection

The evolutionary context adds another layer to this discovery. Human brains are roughly three times larger than chimpanzee brains, requiring careful regulation of cell death during development. The same mutation that made Fas Ligand vulnerable to plasmin may have provided advantages during neural development by reducing premature cell death in brain tissue.

This represents a classic evolutionary trade-off where genetic changes beneficial for one trait carry hidden costs elsewhere. Similar patterns have been observed with other cancer-related genes like p53 and BRCA2, where variations that provide advantages in some contexts increase disease susceptibility in others.

Future Therapeutic Directions

The research team demonstrated that antibodies targeting specific regions of Fas Ligand can protect it from plasmin degradation without interfering with its cancer-killing function. In mouse studies, these protective antibodies successfully restored immune cell effectiveness against plasmin-rich tumors.

The findings suggest that measuring plasmin levels in tumors could help predict which patients might benefit from combination therapies targeting both immune checkpoints and the plasmin system.

“This is a major step toward personalizing and enhancing immunotherapy for the plasmin-positive cancers that have been difficult to treat,” Tushir-Singh said.

The study highlights how understanding our evolutionary history might unlock new approaches to treating diseases that disproportionately affect modern humans.