Expression of Fas and Fas ligand and apoptosis in tumor-associated lymphocytes and in tumor cells from malignant pleural effusions.

Abstract

The CD95 (APO-1/Fas)-Fas ligand (FasL) system is an important mediator of antitumor T cell cytotoxicity. The aim of the current study was to assess its significance in human cancer. Malignant effusions were selected as an environment allowing direct cell-to-cell contact in a fluid phase. Malignant pleural effusions collected from 23 patients with metastatic carcinoma of the bronchus, ovary, stomach or breast were examined by means of flow cytometry. The expression ofFas and FasL, probed with the appropriate antibodies, apoptosis of tumor cells and the characteristics of tumor-associated lymphocytes (TAL) were determined by TUNEL reaction in malignant and nonmalignant (control) effusions. All malignant cells had partially or completely lost the expression of CD95 and expressed an elevated level of FasL. In contrast, TAL obtained from malignant pleural effusions demonstrated a marked decrease in the expression of surface FasL and an increase in surface-bound Fas. The percentage of apoptotic malignant cells was significantly decreased, as compared to TAL and lymphocytes from nonmalignant pleural effusions. There were also differences in the expression of Fas and FasL among mononuclear cells from malignant and nonmalignant pleural effusions. The ability of TAL from malignant pleural effusions to induce apoptosis of K562 cells was diminished, as compared to peripheral blood lymphocytes. Taken together, these data suggest that tumor cells in the microenvironment of malignant pleural effusions can evade immune attack by downregulation of the CD95 receptor and by killing lymphocytes through the expression of FasL. These results confirm earlier reports which showed that lymphocytes from a tumor microenvironment appear to have a depressed cytotoxic action.