Year: 2023
Type: article
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-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.
Source: Cell Reports Medicine
Authors: 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 Pozniak, Fabricio Loayza-Puch, Alexandra M. Terry, Judith Müller, Meike E.W. Logtenberg, Marjolein de Bruijn, Pierre Levy, Pierre-René Körner, Colin R. Goding, Ton N. Schumacher, Jean-Christophe Marine, Reuven Agami, Daniel S. Peeper
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,460
OpenAlex ID: W4321452899