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 certain immune cells, like T cells and natural killer (NK) cells, and prevents them from attacking too aggressively. Cancer cells take advantage of this "brake" to protect themselves from the immune system.
That's why scientists are developing cancer immunotherapy drugs to block TIGIT so the immune system can 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 new findings show that rhesus macaques — but not humans — shed TIGIT from immune cell surfaces when exposed to plasmin. Plasmin is a natural enzyme involved in blood clot breakdown. The enzyme is highly upregulated (increased) in almost all solid cancers.
This shedding creates a soluble form of TIGIT that can still bind anti-TIGIT monoclonal antibodies, such as tiragolumab, an investigational cancer treatment.
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.
"Currently, preclinical safety and dose estimation studies for cancer immunotherapy drugs targeting TIGIT are done in macaques," said Jogender Tushir-Singh, an associate professor in the Department of Medical Microbiology and Immunology and senior author of the study.
"We know from our study of macaque response that the dilution of the drug away from T-cells is a problem. Tests in macaques will not predict proper safety and dose estimation data for human clinical trials," Tushir-Singh said. "It seems like TIGIT biology and mechanism are much 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 easy 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 misleading data
The researchers say more studies are needed, but the findings raise questions for current and future TIGIT-targeted cancer trials. They note that testing TIGIT cancer drugs in macaques could have produced misleading safety and efficacy data. This may help explain why TIGIT therapies have underperformed in late-stage trials.
"The study underscores the need for improved models that better reflect human biology when developing next-generation immunotherapies," Tushir-Singh said.
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).
