Cell reports. Medicine · 2023
An adverse tumor-protective effect of IDO1 inhibition.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Kenski Juliana C N, Huang Xinyao, Vredevoogd David W, de Bruijn Beaunelle, Traets Joleen J H, Ibáñez-Molero Sofía, Schieven Sebastiaan M, van Vliet Alex, Krijgsman Oscar, Kuilman Thomas, Pozniak Joanna, Loayza-Puch Fabricio, Terry Alexandra M, Müller Judith, Logtenberg Meike E W, de Bruijn Marjolein, Levy Pierre, Körner Pierre-René, Goding Colin R, Schumacher Ton N, Marine Jean-Christophe, Agami Reuven, Peeper Daniel S
Аннотация
By restoring tryptophan, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors aim to reactivate anti-tumor T cells. However, a phase III trial assessing their clinical benefit failed, prompting us to revisit the role of IDO1 in tumor cells under T cell attack. We show here that IDO1 inhibition leads to an adverse protection of melanoma cells to T cell-derived interferon-gamma (IFNγ). RNA sequencing and ribosome profiling shows that IFNγ shuts down general protein translation, which is reversed by IDO1 inhibition. Impaired translation is accompanied by an amino acid deprivation-dependent stress response driving activating transcription factor-4 (ATF4)high/microphtalmia-associated transcription factor (MITF)low transcriptomic signatures, also in patient melanomas. Single-cell sequencing analysis reveals that MITF downregulation upon immune checkpoint blockade treatment predicts improved patient outcome. Conversely, MITF restoration in cultured melanoma cells causes T cell resistance. These results highlight the critical role of tryptophan and MITF in the melanoma response to T cell-derived IFNγ and uncover an unexpected negative consequence of IDO1 inhibition.