New research from the UC Davis Comprehensive Cancer Center shows that tiny genetic changes that help the human brain may also make us more vulnerable to cancer.
The study, published in Nature Communications, reveals how single amino acid substitutions in immune proteins called FAS ligands make human anticancer cells less effective against solid tumors than chimpanzees and other nonhuman primates.
Evolutionary trade-offs
Scientists have found that humans have unique mutations in which the amino acid serine is position 153 in the FAS ligand protein replaces proline. This seemingly minor change makes the protein susceptible to disability of cilidin, an enzyme used by tumors to spread throughout the body.
“The evolutionary mutation in FASL may have led to larger brain sizes in humans,” said Jogeender Tushir-Singh, senior author of the study and associate professor in the Department of Medical Microbiology and Immunology. “But in the context of cancer, this is an unfavorable trade-off because the mutation gives some tumors a way to dispel parts of the immune system.”
Research shows that this genetic change contributes to neural development in human evolution, but brings unexpected costs: increasing cancer vulnerability in modern humans.
How tumors take advantage of this weakness
FAS ligands are key weapons for immune cells, triggering cell death programmed in cancer cells through a process called apoptosis. However, the human version of this protein contains structural weaknesses that aggressive tumors can exploit.
In cancers such as triple-negative breast, colon and ovarian cancer, elevated levels of plasmin enzymes can be effectively neutralized before killing tumor cells. This mechanism helps explain why certain immunotherapies can fight blood cancer well, but often struggle with solid tumors.
Researchers found:
- Human FAS ligands are highly susceptible to plasmin cleavage
- Chimpanzees and rhesus versions resist this degeneration
- Tumors with high plasmin levels show greater therapeutic ability
- Blocking plasmin can restore cancer-killing ability of human immune cells
Clinical significance
The discovery provides new strategies to improve cancer treatment. By combining galvanic immunotherapy with plasmin inhibitors or specially designed antibodies that protect FAS ligands, researchers may be able to enhance the immune response against solid tumors.
Tests on patient-derived ovarian cancer cells confirmed that tumors with high plasmin activity were significantly less sensitive to human FAS ligands compared to the primate version. Importantly, blocking plasmin activity restores effectiveness in killing cancer immune cells.
“Human cancer rates are significantly higher than those of chimpanzees and other primates,” Tushir-Singh noted. “We don’t know much, and we can still learn from primates and apply for immunotherapy to improve human cancer.”
Brain connection
The evolutionary context adds another layer to the discovery. The human brain is about three times that of chimpanzees and needs to be carefully regulated during development. Making FAS ligand susceptible to the same mutations of plasmin may have an advantage in neurodevelopment by reducing premature cell death in brain tissue.
This represents a classic evolutionary tradeoff where genetic changes benefit one trait from hidden costs elsewhere. Similar patterns have been observed with other cancer-related genes such as p53 and BRCA2, in some cases, and in some cases the changes that offer advantages increase the susceptibility of the disease.
Future treatment direction
The team showed that antibodies targeting specific regions of the FAS ligand protect it from plasmin degradation without interfering with its cancer killing function. In mouse studies, these protective antibodies successfully restored immune cell effectiveness against fibrin-rich tumors.
The results show that measuring plasmin levels in tumors can help predict which patients may benefit from a combination therapy targeting immune checkpoints and plasmin system.
“This is a major step in personalized and enhanced immunotherapy for difficult-to-treat plasmin-positive cancers,” Tushir-Singh said.
The study highlights how our evolutionary history unlocks new ways to treat diseases that disproportionately affect modern humans.
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