title: Inhibition of indoleamine 2,3-dioxygenase activity enhances the anti-tumour effects of a Toll-like receptor 7 agonist in an established cancer model.
abstract: Toll-like receptor (TLR) agonists have been shown to have anti-tumour activity in basic research and clinical studies. However, TLR agonist monotherapy does not sufficiently eliminate tumours. Activation of the innate immune response by TLR agonists is effective at driving adaptive immunity via interleukin-12 (IL-12) or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, transforming growth factor-β, and indoleamine 2,3-dioxygenase (IDO). In the present study, we evaluated the anti-cancer effect of the TLR7 agonist, imiquimod (IMQ), in the absence of IDO activity. The administration of IMQ in IDO knockout (KO) mice inoculated with tumour cells significantly suppressed tumour progression compared with that in wild-type (WT) mice, and improved the survival rate. Moreover, injection with IMQ enhanced the tumour antigen-specific T helper type 1 response in IDO-KO mice with tumours. Combination therapy with IMQ and an IDO inhibitor also significantly inhibited tumour growth. Our results indicated that the enhancement of IDO expression with TLR agonists in cancer treatment might impair host anti-tumour immunity while the inhibition of IDO could enhance the therapeutic efficacy of TLR agonists via the increase of T helper type 1 immune response.
authors.affiliation: Department of Informative Clinical Medicine, First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ando
authors.forename: Yuko
authors.initials: Y
authors.lastname: Arioka
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
mesh_terms: D000634:Aminoquinolines / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077271:Imiquimod; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D008198:Lymph Nodes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013945:Thymoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000634:Aminoquinolines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D014364:Tryptophan; D000077271:Imiquimod; C525396:1-methyltryptophan
keywords: T helper type 1 response; Toll-like receptor; cancer immunotherapy; imiquimod; indoleamine 2,3-dioxygenase