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Cancer Immunol Immunother. 2011 Jun;60(6):839-45. doi: 10.1007/s00262-011-0998-2. Epub 2011 Mar 9.

Nitric oxide short-circuits interleukin-12-mediated tumor regression.

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1
Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA. negilmez@buffalo.edu

Abstract

Interleukin-12 (IL-12) can promote tumor regression via activation of multiple lymphocytic and myelocytic effectors. Whereas the cytotoxic mechanisms employed by T/NK/NKT cells in IL-12-mediated tumor kill are well defined, the antitumor role of macrophage-produced cytotoxic metabolites has been more controversial. To this end, we investigated the specific role of nitric oxide (NO), a major macrophage effector molecule, in post-IL-12 tumor regression. Analysis of tumors following a single intratumoral injection of slow-release IL-12 microspheres showed an IFN╬│-dependent sevenfold increase in inducible nitric oxide synthase (iNOS) expression within 48 h. Flow cytometric analysis of tumor-resident leukocytes and in vivo depletion studies identified CD11b(+) F4/80(+) Gr1(lo) macrophages as the primary source of iNOS. Blocking of post-therapy iNOS activity with N-nitro-L: -arginine methyl ester (L-NAME) dramatically enhanced tumor suppression revealing the inhibitory effect of NO on IL-12-driven antitumor immunity. Superior tumor regression in mice receiving combination treatment was associated with enhanced survival and proliferation of activated tumor-resident CD8+ T-effector/memory cells (Tem). These findings demonstrate that macrophage-produced NO negatively regulates the antitumor activity of IL-12 via its detrimental effects on CD8+ T cells and identify L-NAME as a potent adjuvant in IL-12 therapy of cancer.

PMID:
21387108
DOI:
10.1007/s00262-011-0998-2
[Indexed for MEDLINE]
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