Study Discovers Genetic Mutation that Makes Solid Tumors Unresponsive to Immunotherapy

While studying why non-human primates aren’t as likely to suffer from certain cancers when compared to humans, UC Davis scientists discovered a genetic mutation that could explain this anomaly. Their findings were published in the Nature Communications journal. This discovery could open the door to the development of more powerful treatments for cancer. 

The researchers focused on Fas Ligand, an immune protein that helps in attacking tumor cells. This protein is present in both human and non-human primates like chimpanzees. The scientists discovered that in humans, a small mutation makes FasL to be easily deactivated by a tumor-linked enzyme called plasmin. This vulnerability is unique to humans because other primates don’t manifest the same weakness. 

The study’s senior author, Tushir-Singh, explains that the FasL mutation in humans happened as part of the evolutionary process and contributed to human brains growing larger than those of other primates. He adds that the benefit of having a bigger brain now appears to have been a tradeoff that was unfavorable to humans since it created an avenue for certain cancers to proliferate and evade treatment. Non-human primates without the FasL mutation exhibit a more effective immune response that wards off those cancers. 

Plasmin, the enzyme that inactivates FasL, is common in aggressive solid tumors, such as ovarian cancer, colon cancer and triple negative breast cancer. 

When the body detects a tumor, the immune system mobilizes to respond to the cancer. FasL, a protein found on membranes of immune cells, works by triggering apoptosis, or programmed cell death. However, when immune cells enter the tumor environment, they encounter plasmin, which deactivates one of the key weapons (FasL) that would help in combating those tumor cells. Consequently, the immune system is less able to deal with the cancerous cells. 

What this means is that advanced cancer therapies like immunotherapy are less effective when dealing with solid tumors that manifest plasmin activity. This could explain why immune therapies work so well against blood cancers but fall short when it comes to solid tumors. Blood cancers don’t usually have plasmin since they don’t need it to metastasize. Solid tumors heavily rely on plasmin for their metastasis. 

This research opens the possibility of developing treatments targeting plasmin in order to keep the immune cells intact and able to combat tumors. Combining immunotherapies with special antibodies trained to protect FasL or using plasmin inhibitors could therefore render immunotherapy treatments more effective than they currently are against solid tumors. 

As more entities, such as Calidi Biotherapeutics Inc. (NYSE American: CLDI), advance their programs aimed at improving immunotherapy success rates, a time could come when solid tumors previously regarded as hard to treat respond well to new treatments and patients get the desired clinical outcomes. 

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