An adverse tumor-protective effect of IDO1 inhibition

Journal article

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.

Authors: Kenski, JCN; Huang, X; Vredevoogd, DW; de Bruijn, B; Traets, JJH

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell Reports Medicine
• Volume: 4
• Issue: 2
• Article number: 100941
• Publication date: 2023-02-21
• Acceptance date: 2023-01-20
• DOI: 10.1016/j.xcrm.2023.100941
• EISSN: 2666-3791
• Language: English
• Keywords: clinical trial; IDO1; melanoma; translation; IDO1 inhibition; FFR; T cells; MITF; immunotherapy; IFNgamma