Malignant mesothelioma is an aggressive tumor of the pleura for which, at present, there is no effective therapy. As interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells lyse many solid tissue malignancies that are unresponsive to conventional forms of therapy, the aim of this study was to evaluate the susceptibility of human malignant mesothelioma cells to lysis by natural killer (NK) and LAK cells. Using a 4-h 51Cr release assay, malignant mesothelioma cell lines grown from six different patients were found to be resistant to NK cell lysis (less than 10% lysis as compared to 50 +/- 3% lysis of the standard NK-sensitive target, K562, p less than 0.001). These malignant mesothelioma cells were, however, susceptible to lysis by LAK cells (58 +/- 4% lysis, p less than 0.001 compared to NK lysis). Similar results were seen using fresh mesothelioma cell targets (4 +/- 2% and 34 +/- 12% lysis for NK and LAK cells, respectively). Optimal LAK cell activation against these targets was achieved by incubating peripheral blood mononuclear cells (2 to 4 x 10(6)/ml) in culture medium containing 1,000 units/ml IL-2 for 3 to 14 days. The degree of LAK cell activation was dependent on the serum source used in culture, with autologous serum being more effective than pooled human AB serum or fetal calf serum at generating LAK cell activity in vitro (p less than 0.05). The results of this study demonstrate that although human malignant mesothelioma cells are resistant to NK cell lysis, IL-2-activated LAK cells effectively kill these targets.(ABSTRACT TRUNCATED AT 250 WORDS)