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

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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
Issue number12
Publication statusPublished - Dec 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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