A recent study from the UC Davis Comprehensive Cancer Center has identified a genetic mutation that may explain why humans are more susceptible to cancer compared to chimpanzees, potentially paving the way for more effective treatments.

The research, published in Nature Communications, focuses on a mutation in the immune protein Fas Ligand (FasL), where a single amino acid change from proline to serine enhances its vulnerability to plasmin, an enzyme that tumors exploit for metastasis.

This mutation represents an evolutionary trade-off, as it may have contributed to human brain development while simultaneously increasing the risk of cancer by compromising immune responses.

Jogender Tushir-Singh, the study's senior author, noted that while this genetic change may have aided in the expansion of human brain size, it has also weakened cancer immunity by allowing tumors to evade immune responses.

Fas Ligand is essential for immune cells to induce programmed cell death in cancer cells, but the human variant is structurally less effective than that found in chimpanzees and other non-human primates.

Elevated levels of plasmin are frequently found in aggressive solid tumors, such as triple-negative breast cancer and colon cancer, where they hinder the effectiveness of treatments by neutralizing FasL.

The study explains the disparity in the effectiveness of immunotherapies like CAR-T and T-cell therapies, which are more successful in treating blood cancers compared to solid tumors that rely on plasmin for metastasis.

Blocking plasmin could restore the cancer-fighting capabilities of human immune cells against solid tumors, suggesting new avenues for treatment.

Combining current cancer treatments with plasmin inhibitors or antibodies that protect FasL could enhance the effectiveness of immunotherapy for solid tumors.

Research has shown that antibodies targeting Fas Ligand can protect it from degradation by plasmin, thereby restoring immune functionality in mouse models, indicating promising therapeutic strategies.

The findings underscore the importance of understanding evolutionary history to develop new treatment strategies for diseases that predominantly affect modern humans.

Overall, this research highlights the critical role of plasmin in aggressive solid tumors and the need for further exploration into primate biology to improve cancer immunotherapy in humans.