The Journal of Cancer Research, 2015. doi: 10.1158/0008-5472.CAN-14-3011


Lisa A Ridnour, Robert YS Cheng, Jonathan M Weiss, et al.

Quansys Products Used:

Human Cytokine High Sensitivity Screen (15-Plex)


Nitric oxide synthases (NOS) are important mediators of pro-growth signaling in tumor cells, as they regulate angiogenesis, immune response, and immune-mediated wound healing. Ionizing radiation (IR) is also an immune modulator and inducer of wound response. We hypothesized that radiation therapeutic efficacy could be improved by targeting NOS following tumor irradiation. Herein, we show enhanced radiation-induced (10 Gy) tumor growth delay in a syngeneic model (C3H) but not immunosuppressed (Nu/Nu) SCC tumor-bearing mice treated post-IR with the constitutive NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). These results suggest a requirement of T cells for improved radiation tumor response. In support of this observation, tumor irradiation induced a rapid increase in the immunosuppressive Th2 cytokine IL-10, which was abated by post-IR administration of L-NAME. In vivo suppression of IL-10 using an anti-sense IL-10 morpholino also extended the tumor growth delay induced by radiation in a manner similar to L-NAME. Further examination of this mechanism in cultured Jurkat T cells revealed L-NAME suppression of IR-induced IL-10 expression, which reaccumulated in the presence of exogenous NO donor. In addition to L-NAME, the guanylyl cyclase inhibitors ODQ and TSP-1 also abated IR-induced IL-10 expression in Jurkat T cells and ANA-1 macrophages, which further suggests that the immunosuppressive effects involve eNOS. Moreover, cytotoxic Th1 cytokines, including IL-2, IL-12p40, and IFN-γ, as well as activated CD8+ T cells were elevated in tumors receiving post-IR L-NAME. Together, these results suggest that post-IR NOS inhibition improves radiation tumor response via Th1 immune polarization within the tumor microenvironment.

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