Inhibition of induced nitric oxide synthase enhances the anti-tumor effects on cancer immunotherapy using TLR7 agonist in mice

Hiroyasu Ito, Tatsuya Ando, Hideyuki Ogiso, Yuko Arioka, Mitsuru Seishima

研究成果: ジャーナルへの寄稿学術論文査読

26 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)429-436
ページ数8
ジャーナルCancer Immunology, Immunotherapy
64
4
DOI
出版ステータス出版済み - 22-03-2015
外部発表はい

All Science Journal Classification (ASJC) codes

  • 免疫アレルギー学
  • 免疫学
  • 腫瘍学
  • 癌研究

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