The tryptophan research community is well aware that the kynurenine pathway contributes to the pathophysiology of neurodegeneration and cancer immunology. In the case of neurodegeneration, the chronic activation of the pathway leading to the production of neuroactive metabolites such as quinolinic acid (QA) has been known to propagate excitotoxicity across several neurodegenerative diseases. In the field of cancer immunology, the Indoleamine 2,3-dioxygenase-1-kynurenine-aryl hydrocarbon receptor (IDO1-kyn-AhR) axis has been a significant target for cancer immunotherapy. The paper highlighted in this feature article focuses on the NMDA agonist QA in cancer immunology, revealing a new role for QA in immuno-oncology.
Kesarwani et al. demonstrated that the kynurenine pathway (KP) is altered in glioblastoma (GBM), leading to the accumulation of QA. The source of increased QA was found to be M2 macrophages, a protumorigenic phenotype, that had a symbiotic relationship with the tumour cells. This is because GBM cells can produce kynurenine from tryptophan but not QA, and M2 macrophages alone are unable to catabolize tryptophan to kynurenine. As a result, they require kynurenine from tumour cells for the production of QA by the M2 macrophages.
In addition, Kesarwani et al. demonstrated that QA can be immunosuppressive by priming macrophages towards an M2-like phenotype. Furthermore, although QA does not affect M1 polarization, it can alter the functionality of M1 macrophages and microglia to mimic M2-like phenotypes, gaining the ability to suppress T-cell proliferation when exposed to QA. The authors further identified the underlying mechanism of macrophage plasticity modulation by QA through NMDAR1 activation, which is present in M2 macrophages but not unpolarized macrophages. This activation leads to Foxo1 phosphorylation and increased PPARĪ³ expression, promoting M2 macrophage polarization. This mechanism differs from the well-known IDO-kyn-AhR-mediated immunosuppression.
Translating this finding into a therapeutic approach, the team then went on to demonstrate that targeting KYNU leads to fewer M2 macrophages, thereby promoting anti-tumor activity. The new role of QA as a promoter of M2 macrophage polarization not only brings a new immunotherapeutic target to the cancer field, highlighting the importance of the kynurenine pathway, but also raises questions about the role of QA in the context of neuroinflammation and whether it may be beneficial rather than detrimental.