April 28, 2022
Principles Behind IDO1 Blockade
The IDO1 enzyme degrades the amino acid tryptophan leading to the production of a number of immunosuppressive metabolites. It comes as no surprise then that many tumor types increase the levels of IDO1 as a means of escaping the hosts’ immune system.
Based on this principle, IDO1 blockade should be an effective immunotherapy strategy in IDO1-overexpressing cancers. Epacadostat was subsequently developed as an orally available, reversible inhibitor of IDO1, but showed lackluster results in randomized clinical trials, and thus, enthusiasm for this line of immunotherapy was dampened.
Why Does IDO1 Blockade Fail?
A recent study published in Science Translational Medicine examined the molecular and metabolic changes that occur with epacadostat treatment in ovarian cancer to understand the underlying mechanism of its clinical inefficacy.
The authors performed complementary transcriptomic, proteomic and metabolic analyses on late stage ovarian cancer samples from 17 patients treated with epacadostat prior receiving surgery, and found that the inhibition of IDO1 by the drug caused increased levels of NAD+ in the tumor microenvironment. Excess NAD+ seemed to reduce T cell proliferation and function- but why?
Combination Therapy Improves Survival in Mouse Models
It turns out that NAD+ metabolites are ligands for a type of receptor called purinergic receptors, and it was their downstream function that suppressed T cell function. The authors then tested the effect of blocking purinergic receptors, namely A2a and A2b, and found that it rescued the effect of NAD+ on T cell proliferation.
The authors then translated these results into a pre-clinical mouse model of IDO1-expressing ovarian cancer, combining epacadostat-mediated IDO1 blockade with the inhibition of purinergic receptors A2a and A2b using the antagonists SCH58261 and PSB1115, respectively. Blocking two types of purinergic receptors and IDO1 improved the immune response against the cancer and the overall survival of mice in the combined treatment group.
Outsourcing Bioinformatics Analysis
This incredible study shows how important it is to leverage the power of bioinformatics and big data analytics to gain actionable biological insights. By utilizing the power of proteomics, transcriptomics and metabolomics, these researchers identified the underlying mechanism for IDO1 blockade failure, and a potential combination therapy to fix it.
These kinds of data analyses require highly specialized, reproducible bioinformatics tools and pipelines. Outsourcing your bioinformatics needs to a service provider like Bridge Informatics can eliminate many of the common challenges associated with storage and analysis of big data in the life sciences. Book a free discovery call to discuss your project needs.
Jane Cook, Journalist & Content Writer, Bridge Informatics
Jane is a Content Writer at Bridge Informatics, a professional services firm that helps biotech customers implement advanced techniques in management and analysis of genomic data. Bridge Informatics focuses on data mining, machine learning, and various bioinformatic techniques to discover biomarkers and companion diagnostics. If you’re interested in reaching out, please email daniel.dacey@old.bridgeinformatics.com or dan.ryder@old.bridgeinformatics.com.
Sources:
https://www.science.org/doi/10.1126/scitranslmed.abg8402
