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

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)429-436
Number of pages8
JournalCancer Immunology, Immunotherapy
Issue number4
Publication statusPublished - 22-03-2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research


Dive into the research topics of 'Inhibition of induced nitric oxide synthase enhances the anti-tumor effects on cancer immunotherapy using TLR7 agonist in mice'. Together they form a unique fingerprint.

Cite this