Many cancers produce an enzyme called IDO that suppresses immune system activity, but the long-held hypothesis of how this mechanism operates requires revision, according to a study published in Clinical Cancer Research.
Rather than depleting the amino acid tryptophan, IDO instead enhances immunosuppressive factors of the complement immune system. This finding explains in part why immunotherapy efforts in incurable cancers such as glioblastoma have fallen flat, according to Derek Wainwright, PhD, assistant professor of Neurological Surgery and senior author of the study.
"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.
Many difficult-to-treat cancers, including glioblastoma, prostate cancer and pancreatic cancer, show high levels of IDO expression. The enzyme converts tryptophan, an essential amino acid that can only be absorbed through diet, into a metabolite called kynurenine. The depletion of tryptophan and the accumulation of kynurenine is the historical mechanism for how IDO suppresses the anti-tumor immune response — primarily based on studies conducted in petri dishes.
"For greater than 20 years, we have assumed this is how IDO affects the immune response," Wainwright said.
Many clinical trials using pharmacologic IDO enzyme inhibitors in combination with immunotherapy have failed to show an improvement in patient survival as compared with immunotherapy alone. This led Wainwright and his collaborators to go back to the drawing board with IDO. In the current study, investigators deleted IDO entirely in mice with cancers similar to glioblastoma, then re-activated IDO, either with a normal form or a form where enzyme activity was nullified.
They found that IDO, regardless of its ability to metabolize tryptophan, was associated with decreased survival of experimental animals with brain tumors and enhanced immunosuppressive cell accumulation.
Glioblastoma. Brown staining indicates IDO expression.
During their 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 where hepatocytes in the liver create a complement factor that binds to invaders or inflamed tissue to help neutralize a pathogen or damaged tissue. Complement factor H (CFH), which normally acts as an inhibitor of the complement cascade to prevent over-activation of complement-mediated protection against foreign invaders, is also regulated by IDO.
CFH is a ripe target for creating new inhibitors that could be deployed alongside immunotherapy, according to Wainwright.Large chemical-genetic screens are now being deployed to identify ligands that can bind to and inhibit CFH with an effort to create a new class of drugs.
This system is poorly studied and the association between IDO and CFH has never been discovered for any cancer prior to our study."
Derek Wainwright, PhD, Senior Author
Wainwright added that this mechanism may be present in other IDO-enriched cancers besides glioblastoma, including pancreatic and prostate cancer.
Lijie Zhai, research assistant professor of Neurological Surgery, was lead author of the study. 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., et al. (2021) Tumor cell IDO enhances immune suppression and decreases survival independent of tryptophan metabolism in glioblastoma. Clinical Cancer Research. doi.org/10.1158/1078-0432.CCR-21-1392.