ID: 24: Inhibition of the TNF-a/NOS2 inflammatory pathway alters nasopharyngeal carcinoma tumor growth

Abstract

We previously showed that in patients, nitric oxide synthase activity (NOS2) promoted nasopharyngeal tumor growth (NPC). Tumor necrosis factor (TNF α ) is a pro-inflammatory cytokine which engages nitric oxide (NO∗) in several carcinogenic processes. In NPC patients, TNF α synthesis associates with poor survival. Here, we aimed at determining whether TNF α signaling inhibition could alter NOS2 dependent NPC growth in vitro. For this purpose, TNF α influence on nitrite production and tumor cell proliferation were analyzed. We observed that monocytes/macrophages (Mo/Ma) and primary tumor biopsies, isolated from patients, synthesized significant amounts of nitrites. Endogenous TNF α neutralization with an anti-TNF α monoclonal antibody (mAb) successfully inhibited nitrites synthesis by Mo/Ma and tumor explants. Recombinant TNF α (rTNF α ) enhanced nitrites synthesis and C666-1 NPC cells proliferation. Treatment with the NOS2 selective inhibitor (1400 W) and an anti-TNF α mAb potently inhibited rTNF α induced C666-1 proliferation and nitrites synthesis. Strikingly, patients tumors explants treated with the anti-TNF α mAb displayed reduced proliferation as indicated by Ki67 index. Altogether, our results define Mo/Ma and the primary tumor as major sources of circulating NO∗ in NPC patients and support the idea that antibody dependent inhibition of the TNF α /NOS2 inflammatory pathway may alter nasopharyngeal carcinoma tumor growth.