Background: In vitro studies have shown an antiproliferative effect of tumor necrosis factor (TNF) against various nonsmall cell lung carcinoma (NSCLC) cell lines. However, clinical trials of combined interleukin-2 and TNF-alpha in patients with advanced NSCLC have demonstrated both conflicting and disappointing results.
Methods: Immunohistochemical (IHC) staining was performed on formalin fixed, paraffin embedded tissues from 39 bronchogenic adenocarcinomas and 32 squamous cell carcinomas using polyclonal antibodies against TNF-alpha, TNF-beta, TNF-R1, and TNF-R2 proteins. IHC positivity was correlated with tumor stage, grade, and patient survival.
Results: Significant coexpression of TNF-alpha, TNF-beta, TNF-R1, and TNF-R2 was observed in NSCLC (significance range, P < 0.001-0.02). Although immunoreactivity for TNFs remained high in all tumor stages, a loss of TNF-R expression was found in advanced NSCLC (P < 0.006 for TNF-R1 and P < 0.003 for TNF-R2), suggesting down-regulation of TNF-Rs in the process of tumor progression. When all stages were considered together, immunoreactivity for TNF-beta(P < 0.001), TNF-R1, and TNF-R2 (both P < 0.001) significantly correlated with favorable outcome in univariate analysis. However, when stages were studied separately, an association between immunopositivity for TNF-Rs and favorable prognosis was found only in NSCLC without distant metastasis (P < 0.04 and P < 0.005 for TNF-R1 and TNF-R2 in Stage I [according to the American Joint Committee on Cancer staging system] disease, and P < 0.03 and P < 0.02 for TNF-R1 and TNF-R2 in Stage III disease). On multivariate analysis, increased expression of TNF-R1 (P < 0.003) and TNF-R2 (P < 0.001) as well as tumor stage (P < 0.001) independently predicted favorable outcome in patients with NSCLC.
Conclusions: Although NSCLC exhibits strong coexpression of TNF-alpha, TNF-beta, TNF-R1, and TNF-R2, there is a loss/down-regulation of TNF receptors in high stage tumors. TNF-R1 and TNF-R2 positivity independently predicts favorable outcome in NSCLC, particularly in tumors with no clinically distant metastasis. The current study supports a role for TNFs and their receptors in the evolution and progression of NSCLC.