Oncotarget

Research Papers:

Inhibition of iNOS activity enhances the anti-tumor effects of alpha-galactosylceramide in established murine cancer model

Hiroyasu Ito _, Tatsuya Ando and Mitsuru Seishima

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Oncotarget. 2015; 6:41863-41874. https://doi.org/10.18632/oncotarget.6172

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Abstract

Hiroyasu Ito1, Tatsuya Ando1 and Mitsuru Seishima1

1 Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan

Correspondence to:

Hiroyasu Ito, email:

Keywords: cancer immunotherapy, alpha-garactosylceramide, induced nitric oxide synthase, tumor antigen-specific immune response, MDSC

Received: May 22, 2015 Accepted: October 06, 2015 Published: October 19, 2015

Abstract

Alpha-garactosylceramide (GalCer) has been shown to have anti-tumor effect in the basic research and clinical studies. However, anti-tumor effect of GalCer is limited. The administration of GalCer increases the production of IFN-γ which is involved in the suppression of tumor growth. On the other hand, the enhancement of IFN-γ production increases immunosuppressive factors such as nitric oxide. This suppressive action might impair the anti-tumor effect of GalCer. In the present study, we evaluated the anti-tumor effect of GalCer in the absence of inducible nitric oxide synthase (iNOS). In lung metastatic model, the number of tumor nodules in the lung of iNOS-KO mice treated with GalCer was significantly reduced compared with that of WT mice treated with GalCer. Moreover, L-NAME, which is the inhibitor for iNOS, enhanced the anti-tumor effect of GalCer in lung metastatic model. The frequency of CD8+ cells in bronchoalveolar lavage fluid increased in iNOS-KO mice treated with GalCer. The administration of GalCer increased the frequency of myeloid-derived suppressor cells (MDSCs) in the lung from tumor-bearing WT mice, but the increase of MDSCs in the lung was not induced in iNOS-KO mice. The subcutaneous tumor experiments revealed that the administration of GalCer in the absence of iNOS expression significantly enhanced the induction of tumor antigen-specific response. Finally, our results indicated that the inhibition of iNOS expression could enhance the therapeutic efficacy of GalCer via the increase of tumor antigen-specific immune response and the suppression of MDSCs.


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