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An adverse tumor-protective effect of IDO1 inhibition

2023; Elsevier BV; Volume: 4; Issue: 2 Linguagem: Inglês

10.1016/j.xcrm.2023.100941

2666-3791

Juliana C.N. Kenski, Xinyao Huang, David W. Vredevoogd, Beaunelle de Bruijn, Joleen J.H. Traets, Sofía Ibáñez-Molero, Sebastiaan M. Schieven, Alex van Vliet, Oscar Krijgsman, Thomas Kuilman, Joanna Poźniak, Fabricio Loayza‐Puch, Alexandra M. Terry, Judith M. Müller, Meike E. W. Logtenberg, Marjolein de Bruijn, Pierre Lévy, Pierre-René Körner, Colin R. Goding, Ton N. Schumacher, Jean‐Christophe Marine, Reuven Agami, Daniel S. Peeper,

Immune cells in cancer

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.