title: Inhibition of induced nitric oxide synthase enhances the anti-tumor effects on cancer immunotherapy using TLR7 agonist in mice.
abstract: Toll-like receptor (TLR) agonists have been shown to have anti-tumor activity in basic research and clinical studies. However, TLR agonist monotherapy in cancer treatment dose not sufficiently eliminate tumors. Activation of the innate immune response by TLR agonists and other pathogen-associated molecular patterns is effective for driving adaptive immunity via interleukin (IL)-12 or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, tumor growth factor-β, and induced nitric oxide synthase (iNOS). In the present study, we evaluated the anticancer effect of the TLR7 agonist, imiquimod (IMQ), in the absence of iNOS. The administration of IMQ in iNOS-knockout (KO) mice implanted with tumor cells significantly suppressed tumor progression as compared to that in wild-type mice and improved the survival rate. Moreover, injection with IMQ enhanced the tumor antigen-specific Th1 response in iNOS-KO mice with tumors. The enhancement of the antigen-specific Th1 response was associated with an increase in IL-2 and IL-12b expressions in the tumor-draining lymph nodes. Combination therapy with IMQ and an iNOS inhibitor also significantly inhibited tumor growth in the established tumor model. Finally, our results indicated that the enhancement of iNOS expression through the administration with TLR agonists impairs host anti-tumor immunity, while the inhibition of iNOS could enhance the therapeutic efficacy of TLR agonists via the increase in Th1 immune response.
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan, hito@gifu-u.ac.jp.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ando
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ogiso
authors.forename: Yuko
authors.initials: Y
authors.lastname: Arioka
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D000077271:Imiquimod; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D014407:Tumor Cells, Cultured
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D016207:Cytokines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000077271:Imiquimod