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

Abstract

Targeted delivery of IFNgamma to tumors has been achieved by fusing this cytokine with GCNGRC, a tumor neovasculature homing peptide. Although the therapeutic efficacy of this protein (called IFNgamma-NGR) in animal models is greater than that of IFNgamma, frequent administrations of IFNgamma-NGR may result in lower efficacy and tumor resistance. We investigated the role of indoleamine 2,3-dioxygenase (IDO), an IFNgamma-inducible enzyme that may down-regulate T cells by affecting local tryptophan catabolism in tumor resistance to repeated treatments with IFNgamma-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 IFNgamma-NGR but not after a single treatment. Coadministration of 1-methyl-tryptophan, an inhibitor of IDO, increased tumor responses to multiple treatments in the lymphoma, melanoma, and fibrosarcoma models. No synergism between IFNgamma-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 IFNgamma-NGR, likely causing excessive stimulation of tryptophan catabolism and inhibiting antitumor immune mechanisms. Coadministration of IFNgamma-NGR with IDO inhibitors could represent a new strategy for increasing its antitumor activity.

• Authors: Anna Maria Gasparri, Elena Jachetti, Barbara Colombo, Angelina Sacchi, Flavio Curnis, Gian-Paolo Rizzardi, Catia Traversari, Matteo Bellone, Angelo Corti
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 12 Pg. 3859-66 (Dec 2008) ISSN: 1535-7163 [Print] United States
• PMID: 19074858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• IFNgamma-NGR peptide
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Recombinant Fusion Proteins
• Interferon-gamma
• Tryptophan

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (pharmacology)
• Interferon-gamma (metabolism, physiology)
• Melanoma, Experimental
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Neoplasms (drug therapy, pathology)
• Recombinant Fusion Proteins (chemistry, pharmacology)
• Tryptophan (analogs & derivatives, pharmacology)