SACRAMENTO, Calif. — Groundbreaking research conducted by the University of California, Davis Comprehensive Cancer Center has revealed significant insights into why human immune cells exhibit reduced effectiveness against solid tumors when compared to their non-human primate counterparts. This research holds potential implications for developing more effective cancer treatments in the future.

The study, published in the esteemed journal Nature Communications, identified a critical genetic difference in a protein known as Fas Ligand (FasL) that is present in the immune systems of humans and non-human primates. This small genetic alteration renders the FasL protein more susceptible to deactivation by plasmin, an enzyme typically associated with tumors. Notably, this vulnerability appears to be exclusive to humans, with non-human primates like chimpanzees not exhibiting the same susceptibility.

According to Jogender Tushir-Singh, the senior author of the study and an associate professor in the Department of Medical Microbiology and Immunology, “The evolutionary mutation in FasL may have contributed to the larger brain size in humans. However, in the context of cancer, this mutation represents an unfavorable tradeoff, as it provides certain tumors with a mechanism to disarm elements of our immune defense.”

The FasL protein plays a pivotal role in the immune response by triggering a process known as apoptosis, or programmed cell death. This process is crucial for eliminating cancer cells. The research team at UC Davis found that in humans, a single amino acid change—where serine replaces proline at position 153—makes FasL more vulnerable to being cleaved and inactivated by plasmin.

Plasmin is a protease enzyme that is frequently found in elevated levels within aggressive solid tumors, including types like triple-negative breast cancer, colon cancer, and ovarian cancer. As a consequence, even when human immune cells are primed and ready to combat tumor cells, the tumor environment can neutralize their primary mechanism of action—FasL—significantly diminishing the effectiveness of immunotherapies.

This discovery may provide clarity as to why therapies utilizing CAR-T cells and other T-cell-based approaches are often effective against blood cancers yet struggle in treating solid tumors. Blood cancers generally do not depend on plasmin for metastasis, while solid tumors, such as ovarian cancer, heavily rely on plasmin for spreading malignancy.

Furthermore, the study illuminated a pathway for potential therapeutic advancements. The researchers demonstrated that inhibiting plasmin or protecting FasL from cleavage could restore its ability to kill cancer cells. This revelation may lead to novel strategies for enhancing cancer immunotherapy.

By integrating current treatment modalities with plasmin inhibitors or specially designed antibodies that safeguard FasL, it is conceivable that oncologists could amplify immune responses in patients grappling with solid tumors.

“Humans experience a vastly higher incidence of cancer compared to chimpanzees and other non-human primates,” Tushir-Singh stated. “There’s still much we can learn from studying primates that could enhance human cancer immunotherapies. Nonetheless, this represents a significant milestone in the pursuit of personalized and enhanced immunotherapy for challenging plasmin-positive cancers.”

A comprehensive list of coauthors and funding sources can be found in the original article.