Induction of inflammatory cytokines in effusion cavity by OK-432 injection therapy for patients with malignant effusion: role of interferon-gamma in enhancement of surface expression of ICAM-1 on tumor cells in vivo.

The intracavitary injection of OK-432, a streptococcal preparation, has been shown to be an effective immunotherapy for patients with malignant effusion. We found that this therapy increases surface expression of intercellular adhesion molecule-1 (ICAM-1) on tumor cells, and that the degree of increased ICAM-1 was correlated with therapeutic effects. In the present study, we investigated the ability of OK-432-induced inflammatory cytokines, such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta), to enhance ICAM-1 expression. We treated 17 patients who had a malignant effusion with OK-432. At 24 hr after OK-432 injection, ICAM-1 levels on tumor cells were increased significantly in responders except in one case (n=9), whereas no change was evident in nonresponders except in two cases (n=8). Induced maximum levels of IFN-gamma in responders were significantly higher than those in nonresponders. In contrast, there was no significant difference in the induced TNF-alpha or IL-1 beta levels between the two groups. Two types of cultured tumor cells derived from responder patients were successfully established from the 17 different tumor cells in effusion. We performed an in vitro study using these cultured tumor cells. Treatment of the two cultured tumor cells with recombinant IFN-gamma, but not recombinant TNF-alpha or IL-1 beta, significantly increased their ICAM-1 expression to a clinically detectable level. Direct treatment of the tumor cells with cell-free effusion samples obtained from the same patients 24 hr after the therapy successfully increased ICAM-1 expression and this action was blocked completely only by a pretreatment with anti-IFN-gamma mAb. Our results suggests that in this therapy IFN-gamma plays a crucial role in enhancing ICAM-1 expression by tumor cells and that induced IFN-gamma levels may be a useful marker for evaluation of the therapeutic effect.