Inhibition of iNOS activity enhances the anti-tumor effects of alpha-galactosylceramide in established murine cancer model.
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.
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan.
Hiroyasu
H
Ito
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan.
Tatsuya
T
Ando
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan.
Mitsuru
M
Seishima
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005699:Galactosylceramides / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D000951:Antigens, Neoplasm; D016207:Cytokines; D004791:Enzyme Inhibitors; D005699:Galactosylceramides; C493154:alpha-galactosylceramide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019331:NG-Nitroarginine Methyl Ester
MDSC; alpha-garactosylceramide; cancer immunotherapy; induced nitric oxide synthase; tumor antigen-specific immune response