Many cancers produce an enzyme called IDO which blocks immune system activity The long-held notion of how this mechanism functions needs to be revised, according to a study published in Clinical Cancer Research.
Rather than depleting tryptophan’s amino acid, IDO instead enhances immunosuppressive factors in the complement immune system. This may be the reason the efforts to treat incurable cancers with immunotherapy such as glioblastoma are not effective, according to Derek Wainwright PhD, assistant professor of Neurological Surgery and the lead author.
“We have opened up new possibilities in understanding how IDO suppresses the anti-cancer immune response, independent of its historical and predominant association with tryptophan metabolism,” said Wainwright, who is also a professor of Medicine in the Division of Hematology and Oncology and of Microbiology-Immunology.
The high levels of IDO expression are seen in a wide range of difficult-to-treat cancer, such as glioblastoma and prostate cancer. The enzyme converts tryptophan an essential amino acid that can only be taken in through diet, into a metabolite called kynurenine. The depletion and accumulation of tryptophan, as well as the accumulation of kynurenine is the underlying mechanism behind how IDO inhibits the immune response. This is mostly based on research conducted in petri dishes.
Wainwright said that this is the way IDO affects the immune system for more than 20 years.
Many clinical trials using the pharmacologic IDO enzyme inhibitors in combination with immunotherapy have failed show an improvement in patient survival when compared to immunotherapy by itself. Wainwright and his colleagues decided to reevaluate IDO. In the current study, investigators deleted IDO entirely in mice with cancers that resembled glioblastoma. They and then reactivated IDO, either with normal forms or one in which enzyme activity was nullified.
They found that IDO regardless of its capacity to metabolize tryptophan, was associated with a lower survival of experimental animals with brain tumors and increased immune-suppressive cell growth.
Glioblastoma. Brown staining is a sign of IDO expression.
During their investigation of IDO in tumor cells, one particular pathway was noticed by them: the complement cascade. The complement cascade is part of the immune system, which is where hepatocytes in the liver create the complement factor, which is able to bind to invaders or inflamed tissues to neutralize a pathogen or damaged tissue. IDO regulates the complement factor H (CFH) which acts as an inhibitor to the complement cascade, preventing overload of complement-mediated defense against foreign invaders.
Wainwright states that CFH is a major target for new inhibitors.
This system is poorly studied and the relationship between IDO and CFH has not been established for any cancer prior to our study.”
Derek Wainwright, PhD, Senior Author
Wainwright said that this mechanism could be present in other IDO-enriched forms of cancers, including prostate or pancreatic cancer.
Lijie Zhai is the lead author. She is a researcher and assistant professor of Neurological Surgery. Co-authors include Gary Schiltz, PhD, research professor of Pharmacology; Rimas Lukas, MD associate professor in the Ken and Ruth Davee Department of Neurology Division of Neuro-oncology; and Craig Horbinski, MD, PhD director of the Division of Neuropathology in the Department of Pathology and a professor of Neurological Surgery.
Zhai, L., Zhai, L.. (2021) Tumor cell IDO increases the immune system and reduces survival, independent of tryptophan metabolism in the glioblastoma. Clinical Cancer Research. doi.org/10.1158/1078-0432.CCR-21-1392.
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