Critical role of indoleamine 2,3-dioxygenase in tumor resistance to repeated treatments with targeted IFNγ

Anna Maria Gasparri, Elena Jachetti, Barbara Colombo, Angelina Sacchi, Flavio Curnis, Gian Paolo Rizzardi, Catia Traversari, Matteo Bellone, Angelo Corti

Research output: Contribution to journalArticlepeer-review

Abstract

Targeted delivery of IFNγ to tumors has been achieved by fusing this cytokine with GCNGRC, a tumor neovasculature homing peptide. Although the therapeutic efficacy of this protein (called IFNγ-NGR) in animal models is greater than that of IFNγ, frequent administrations of IFNγ-NGR may result in lower efficacy and tumor resistance. We investigated the role of indoleamine 2,3-dioxygenase (IDO), an IFNγ-inducible enzyme that may down-regulate T cells by affecting local tryptophan catabolism in tumor resistance to repeated treatments with IFNγ-NGR. The study was carried out in immunocompetent mice and in nu/nu mice bearing RMA lymphoma, B16F melanoma, or WEHI-164 fibrosarcoma and in vitro using cultured tumor cells. IDO activity was increased in lymphoma homogenates after multiple treatments with IFNγ-NGR but not after a single treatment. Coadministration of 1-methyltryptophan, an inhibitor of IDO, increased tumor responses to multiple treatments in the lymphoma, melanoma, and fibrosarcoma models. No synergism between IFNγ-NGR and 1-methyl-tryptophan was observed in vitro in tumor cell proliferation assays or in nu/nu tumor-bearing mice, suggesting that the antitumor effect was host mediated. We conclude that IDO is critically involved in tumor resistance to repeated treatments with IFNγ-NGR, likely causing excessive stimulation of tryptophan catabolism and inhibiting antitumor immune mechanisms. Coadministration of IFNγ-NGR with IDO inhibitors could represent a new strategy for increasing its antitumor activity.

Original languageEnglish
Pages (from-to)3859-3866
Number of pages8
JournalMolecular Cancer Therapeutics
Volume7
Issue number12
DOIs
Publication statusPublished - Dec 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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