Ovarian cancer-induced immunosuppression: Relationship to tumor necrosis factor-alpha (TNF-alpha) release from ovarian tissue

Cytokines have been reported to be potential biological markers of, disease status in cancer patients. Tumor necrosis factor-alpha (TNF-alpha) is a ke y cytokine released from monocytes and macrophages. TNF-alpha is involved i n essential biological functions such as immunoregulation, modulation of ce ll growth and differentiation. In this work the role of TNF-alpha release i n ol,arian cancer patients was investigated. Fifty-five patients with ovari an cancer and 20 controls of matched age and parity were included in this s tudy. TNF-alpha concentrations were measured in sera and cytosolic fraction s of both groups. The results demonstrated a significant increase in TNF-al pha concentrations among patients compared to the control subjects (P < 0.0 01). Furthermore, a non-significant increase (P = 0.05) was observed betwee n the different types (serous, Mucinous, and endometroid) of epithelial ova rian cancers. Also TNF-alpha concentrations did not correlate with the dise ase stage. Moreover, immunohistochemical analysis of tissue specimens stain ed for TNF-alpha was positive in malignant lesions and negabve for the norm al ovarian tissue. These findings confirmed rite TNF-alpha kinetics obtaine d by ELISA assays. Interestingly, TNF-alpha levels were also elevated in cu lture supematants of PBMC stimulated by cytosolic fractions from malignant ovarian tissues. Blastogenic assays using cytosolic fractions from malignan t ovarian specimens to stimulate healthy donor peripheral blood mononuclear cells (PBMC) showed a marked decrease in H-3-thymidine uptake compared to the cells stimulated by nommal cytosols. To establish a cause-effect relati onship between TNF-alpha release and inhibition of cell proliferation, the experiments showed that H-3-thymidine uptake by PBMC was markedly inhibited by recombinant human TNF-alpha (rh TNF-alpha) and that inhibition Mns sign ificantly reversed when TNF-alpha monoclonal antibody was added to the cell s. The data presented in this work indicate that TNF-alpha may play an impo rtant role in the biology of ovarian cancer and hence, tumor pathogenesis.