An adverse tumor-protective effect of IDO1 inhibition.
Kenski JCN., Huang X., Vredevoogd DW., de Bruijn B., Traets JJH., Ibáñez-Molero S., Schieven SM., van Vliet A., Krijgsman O., Kuilman T., Pozniak J., Loayza-Puch F., Terry AM., Müller J., Logtenberg MEW., de Bruijn M., Levy P., Körner P-R., Goding CR., Schumacher TN., Marine J-C., Agami R., Peeper DS.
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.