Critical role of indoleamine 2,3-dioxygenase in tumor resistance to repeated treatments with targeted IFNgamma.
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.
Gasparri
Anna Maria
AM
Department of Oncology, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy.
Jachetti
Elena
E
Colombo
Barbara
B
Sacchi
Angelina
A
Curnis
Flavio
F
Rizzardi
Gian-Paolo
GP
Traversari
Catia
C
Bellone
Matteo
M
Corti
Angelo
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology*; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
D000970:Antineoplastic Agents; C534881:IFNgamma-NGR peptide; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D014364:Tryptophan