A new study published in the Journal of Biological Chemistry from UC Davis Comprehensive Cancer Center finds that TIGIT, an immune checkpoint receptor targeted by cancer immunotherapy drugs, triggers a different response in rhesus macaques compared to humans.
The findings could have implications for cancer immunotherapy drugs targeting TIGIT.
TIGIT acts like a brake on the immune system
TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a "brake" on the immune system. It sits on immune cells, such as T cells and natural killer (NK) cells, and prevents them from attacking too aggressively. Cancer cells exploit this "brake" to evade the immune system.
That's why scientists are developing cancer immunotherapy drugs to block TIGIT, enabling the immune system to fight tumors more effectively.
However, multiple anti-TIGIT antibodies have failed in Phase III trials for solid tumors, raising questions about the underlying mechanism.
Rhesus macaques "shed" TIGIT from immune cells
The study's findings show that rhesus macaques — but not humans — shed TIGIT from the surfaces of immune cells when exposed to plasmin. Plasmin is a natural enzyme involved in the breakdown of blood clots. The enzyme is highly upregulated (increased) in almost all solid cancers.
Previous research has shown that primates are less vulnerable to cancer than humans. TIGIT shedding is a natural mechanism in monkeys that removes TIGIT-mediated brakes that could lead to cancer and infectious disease. Although TIGIT adds a regulatory brake to fine-tune the human immune response, the evolutionary TIGIT mutation is associated with increased cancer risk in humans.
In the context of cancer therapeutics, the TIGIT shedding creates a soluble form of TIGIT that can still bind anti-TIGIT monoclonal antibodies, such as tiragolumab, a cancer treatment antibody that failed in clinical trials
The result is that in macaques, antibodies may be soaked up by free-floating TIGIT instead of blocking immune suppression on the tumor-fighting cells.
"We know from our study that the dilution of the drug away from T-cells in macaques may not predict safety and dose estimation data for human clinical trials," said Jogender Tushir-Singh, an associate professor in the Department of Medical Microbiology and Immunology and senior author of the study. Tushir-Singh said. "TIGIT biology may be more complex than expected."
Difference in amino acid makes it easier for plasmin to cut TIGIT
The researchers looked at TIGIT proteins from humans and monkeys.
They made lab versions of these proteins and exposed them to plasmin to see what would happen.
They found that in monkeys, a single difference in the protein's amino acid compared to humans (at position 119) made it easier for plasmin to cut TIGIT.
When they added plasmin to human and monkey immune cells, only the monkey cells shed TIGIT from their surfaces. They then checked whether the shed TIGIT in monkeys could still stick to cancer drugs — and it could.
TIGIT testing in macaques may produce unreliable data
The researchers say more studies are needed, but the findings provide insights for current and future TIGIT-targeted cancer trials. They note that testing TIGIT cancer drugs in macaques may have produced unreliable safety and efficacy data. This may help explain why TIGIT therapies have underperformed in late-stage trials.
Coauthors on the study include Eric Pirillo, Francis Freenor V, Brice E.N. Wamba, Sanchita Bhatnagar and Tanmoy Mondal of UC Davis Department of Medical Microbiology and Immunology.
The research was funded by the National Institutes of Health National Cancer Institute (R01CA233752) and the Ovarian Cancer Alliance of Greater Cincinnati (SP0A243532).
Resources
- Read the study
- A single genetic mutation may have made humans more vulnerable to cancer than chimpanzees
- Researchers identify 'switch' to activate cancer cell death
- UC Davis Health Comprehensive Cancer Center
