TNFα antagonization alters NOS2 dependent nasopharyngeal carcinoma tumor growth

- The tumor and the circulating blood monocular cells synthesize NO2− in NPC patients.
- Anti-TNFα inhibits NO2− synthesis by patient's primary NPC tumors and blood mononuclear cells.
- rTNFα mediates C666-1 NPC cell proliferation.
- Anti-TNFα treatment inhibits C666-1 cell proliferation in a NOS2 dependent fashion.
- Anti-TNFα mAb treatment inhibits primary tumor growth.

Tumor necrosis factor (TNFα) is a pro-inflammatory cytokine which mediates via nitric oxide (NO) several carcinogenic processes. Increasing evidences suggest that NO promotes inflammation induced growth of nasopharyngeal carcinoma (NPC). In patients, TNFα synthesis associates with poor survival. To explore the effect of the cytokine on NO production and NOS2 dependent NPC growth, NO2− (nitrite) producing cells in patients were analyzed in vitro. We observed that patients' monocytes/macrophages (Mo/Ma) and primary tumor biopsies synthesized significant amounts of NO2−. Interestingly, tumor explants derived NO2− levels were more important in elderly patients in comparison with juveniles. Endogenous TNFα neutralization with an anti-TNFα monoclonal antibody (mAb) successfully inhibited NO2− synthesis by blood mononuclear cells and tumor explants. Recombinant TNFα (rTNFα) enhanced NO2− synthesis and C666-1 NPC cell proliferation. NOS2 selective inhibition (1400W) and TNFα antagonization with an anti-TNFα mAb potently inhibited rTNFα induced C666-1 proliferation and NO2− production. Importantly, primary tumors treated with the anti-TNFα mAb also displayed reduced proliferation index (Ki67). Altogether, our results define monocytes/macrophages and the primary tumor as major sources of circulating NO2− in NPC patients and support the idea that antibody dependent inhibition of the TNFα/NOS2 pathway may alter NPC tumor growth.