Many cancers produce an enzyme called IDO that suppresses the activity of the immune system, and a long-standing hypothesis about how this mechanism works is Clinical cancer research..
IDO enhances complement immunosuppressive factors in addition to being involved in tryptophan metabolism Immune system.. According to Dr. Derek Wayne Wright, an assistant professor of neurosurgery and lead author of the study, the findings explain some of the reasons why immunotherapy efforts in refractory cancers such as glioblastoma have leveled off. It may be.
“We have opened up new possibilities for understanding how IDO suppresses rebellion.cancer Immune response This has nothing to do with the historical and predominant association with tryptophan metabolism, “said Wayne Wright, a professor of medicine in the Department of Hematology and Microbiology-Immunology.
Many difficult-to-treat cancers, such as glioblastoma, prostate cancer, and pancreatic cancer, show high levels of IDO expression.The enzyme converts tryptophan Essential amino acids It is absorbed only through the diet by a metabolite called kynurenine. Tryptophan depletion and kynurenine accumulation are historical mechanisms of how IDO suppresses the antitumor immune response, based primarily on studies conducted in Petri dishes.
“For over 20 years, we’ve been imagining how IDO affects the immune response,” says Wainwright.
Many clinical trials using pharmacological IDO enzyme inhibitors in combination with immunotherapy have failed to show improved patient survival compared to immunotherapy alone. This led Wayne Wright and his collaborators to use IDO to return to the design drawing. In the current study, researchers completely abolished IDO in mice with cancer similar to glioblastoma and reactivated IDO either in its normal form or in a form in which enzyme activity was abolished. ..
They found that IDO was associated with reduced survival in laboratory animals, regardless of their ability to metabolize tryptophan. Brain tumor Promotes the accumulation of immunosuppressive cells.
During the investigation of IDO in tumor cells, one particular pathway caught their attention: the complement cascade. The complement cascade is part of the basic innate immune system that produces complement factors that help liver hepatocytes bind to invaders or inflamed tissue to neutralize pathogens or damaged tissue. Factor H (CFH) normally acts as an inhibitor of the complement cascade, preventing overactivation of complement-mediated protection against foreign invaders, but is also regulated by IDO.
According to Wayne Wright, CFH is a ripe target for creating new inhibitors that can be deployed in parallel with immunotherapy. Extensive chemo-genetic screening is currently underway to identify ligands that can bind and inhibit CFH to create a new class of drugs.
“This system has not been well studied and the link between IDO and CFH has not been discovered for any cancer prior to our study,” Wayne Wright said.
Wayne Wright added that this mechanism may also be present in other IDO-rich cancers other than glioblastoma, such as pancreatic and prostate cancers.
Lijie Zhai et al, tumor cell IDO, enhances immunosuppression and reduces survival, independent of tryptophan metabolism in glioblastoma. Clinical cancer research (2021). DOI: 10.1158 / 1078-0432.CCR-21-1392
Quote: Https: //medicalxpress.com/news/2021-09-theory-cancer-duced-immune-suppression.html Revised theory of cancer-induced immunosuppression obtained on September 30, 2021 (9 2021) 30th of March)
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