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

作者：Egilmez Nejat K^*; Harden Jamie L; Virtuoso Lauren P; Schwendener Reto A; Kilinc Mehmet O

来源：Cancer Immunology, Immunotherapy, 2011, 60(6): 839-845.

DOI：10.1007/s00262-011-0998-2

• Tumor
• Immune therapy
• Interleukin-12
• iNOS
• Nitric oxide
• CD8+T cell

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 gamma-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.

• 出版日期2011-6