An evil axis

Ludwig MSK’s Jedd Wolchok, Taha Merghoub and their colleagues described the mechanism by which the aryl hydrocarbon receptor (AHR) suppresses anti-tumor immune responses in tumors that express high levels of IDO and TDO, enzymes associated with immune suppression in a wide variety of cancers. The study, reported in an August paper in Nature Communications, found that AHR signaling is selectively activated in such tumors and examined the effects of its inhibition. A product of IDO/TDO activity, L-kynurenine, interacts with AHR in the tumor microenvironment to drive the generation of suppressive immune cells—regulatory T cells (Tregs) and myeloid derived suppressor cells—and prompts killer T cells to express PD-1, which dampens their anti-tumor activity. Jedd, Taha and their colleagues showed that the AHR signaling pathway drives resistance to immune checkpoint blockade. This mechanism of immune suppression, they found, stems from an interplay between Tregs and tumor-associated macrophages. Targeting this axis with an AHR inhibitor reverses IDO/TDO-mediated immune suppression and slows tumor growth in mice. This effect is amplified when the treatment is combined with PD-1 blockade immunotherapy, suggesting the combination should be tested in a clinical trial and could be a basis of personalized medicine for patients with tumors expressing IDO, TDO or showing IDO/TDO-Kyn-AhR pathway activation.

This article appeared in the December 2020 issue of Ludwig Link. Click here to download a PDF (1 MB).


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