AI Article Synopsis
- Increased tryptophan (Trp) breakdown in tumors leads to immune suppression, primarily through the enzymes IDO1 and TDO, and the resulting accumulation of kynurenine (Kyn) is believed to play a key role in this process.
- A new treatment using PEGylated kynureninase (PEG-KYNase) effectively breaks down Kyn into harmless byproducts, which helps inhibit tumor growth and boosts the presence of active immune cells.
- When used alongside existing cancer therapies like checkpoint inhibitors or vaccines, PEG-KYNase shows significant therapeutic benefits in various cancer models, effectively countering the immune-suppressive effects associated with Trp metabolism in the tumor microenvironment.
Article Abstract
Increased tryptophan (Trp) catabolism in the tumor microenvironment (TME) can mediate immune suppression by upregulation of interferon (IFN)-γ-inducible indoleamine 2,3-dioxygenase (IDO1) and/or ectopic expression of the predominantly liver-restricted enzyme tryptophan 2,3-dioxygenase (TDO). Whether these effects are due to Trp depletion in the TME or mediated by the accumulation of the IDO1 and/or TDO (hereafter referred to as IDO1/TDO) product kynurenine (Kyn) remains controversial. Here we show that administration of a pharmacologically optimized enzyme (PEGylated kynureninase; hereafter referred to as PEG-KYNase) that degrades Kyn into immunologically inert, nontoxic and readily cleared metabolites inhibits tumor growth. Enzyme treatment was associated with a marked increase in the tumor infiltration and proliferation of polyfunctional CD8 lymphocytes. We show that PEG-KYNase administration had substantial therapeutic effects when combined with approved checkpoint inhibitors or with a cancer vaccine for the treatment of large B16-F10 melanoma, 4T1 breast carcinoma or CT26 colon carcinoma tumors. PEG-KYNase mediated prolonged depletion of Kyn in the TME and reversed the modulatory effects of IDO1/TDO upregulation in the TME.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078800 | PMC |
| http://dx.doi.org/10.1038/nbt.4180 | DOI Listing |
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