An adverse tumor-protective effect of IDO1 inhibition.

ABSTRACT: 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-cel

SUBMITTER: Kenski JCN 

PROVIDER: S-EPMC9975322 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature