In DepthBiomedicine

A new cancer immunotherapy suffers a setback

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Science  11 May 2018:
Vol. 360, Issue 6389, pp. 588
DOI: 10.1126/science.360.6389.588

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  • Indoleamine 2,3-dioxygenase inhibition in cancer immunotherapy; still a black-box

    Clinical trials with indoleamine 2,3-dioxygenase (IDO) inhibitors in cancer immunotherapy were initially failed (1). The comment of the professor Michael Platten that IDO is still a black box was very purposeful.
    Generally, IDO is thought to suppress T-cell immune response by acting on two systems. The tryptophan degradation product kynurenine activates aryl-hydrocarbon receptor (AhR), which promotes T-cell differentiation towards a regulatory phenotype (2). In parallel, in the microenvironment of the immune response tryptophan depletion activates general control non-derepressible 2 kinase (GCN2K), which decreases T-cell proliferation and induces T-cell apoptosis (3). However, most of these conclusions were extrapolated under the strictly controlled conditions of cell cultures.
    When a free fatty acid is added in the culture medium, the trend for T-cell differentiation towards a regulatory phenotype is not altered, but the anti-proliferative and pro-apoptotic properties of IDO disappear (4). The reason relies on the effect of IDO on T-cell metabolism. Depletion of tryptophan by activating GCN2K decreases glucose and glutamine catabolism. However, kynurenine by activating AhR increases free fatty acid β-oxidation, which refuels T-cells with energy, allowing their proliferation and preventing their apoptosis (5). According to these results, two of the three ways by which IDO is supposed to suppress T-cell-mediated immune response may not take place in the cancer...

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    Competing Interests: None declared.