2. Academic Validation
  3. An adverse tumor-protective effect of IDO1 inhibition

An adverse tumor-protective effect of IDO1 inhibition

  • Cell Rep Med. 2023 Feb 21;4(2):100941. doi: 10.1016/j.xcrm.2023.100941.
Juliana C N Kenski 1,  Xinyao Huang 1,  David W Vredevoogd 1,  Beaunelle de Bruijn 1,  Joleen J H Traets 1,  Sofía Ibáñez-Molero 1,  Sebastiaan M Schieven 1,  Alex van Vliet 1,  Oscar Krijgsman 1,  Thomas Kuilman 1,  Joanna Pozniak 2,  Fabricio Loayza-Puch 3,  Alexandra M Terry 1,  Judith Müller 1,  Meike E W Logtenberg 1,  Marjolein de Bruijn 1,  Pierre Levy 1,  Pierre-René Körner 3,  Colin R Goding 4,  Ton N Schumacher 1,  Jean-Christophe Marine 2,  Reuven Agami 3,  Daniel S Peeper 5
Affiliations

Affiliations

  • 1 Division of Molecular Oncology and Immunology, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
  • 2 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 3 Division of Oncogenomics, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
  • 4 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Headington, OX OX3 7DQ, UK.
  • 5 Division of Molecular Oncology and Immunology, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: d.peeper@nki.nl.
PMID: 36812891 DOI: 10.1016/j.xcrm.2023.100941
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.

Keywords

IDO1; IDO1 inhibition; IFNgamma; MITF; T cells; clinical trial; immunotherapy; melanoma; translation.

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