INVOLVEMENT OF LEUKOCYTE (BETA-2) INTEGRINS (CD18/CD11) IN HUMAN MONOCYTE TUMORICIDAL ACTIVITY

Appropriately activated mononuclear phagocytes mediate contact-dependent tumoricidal activity. Adhesion structures involved in contact-dependent tumor cytotoxicity have not been defined. The present study was aimed at identifying the adhesion structures involved in the tumoricidal activity of activated (IFN-gamma + LPS) human monocytes. Tumor cells of different histological origin were used as targets in a 48-hr cytolysis assay. Anti-CD18 (integrin beta-2 chain) monoclonal antibodies (MAbs) substantially (50-80%) inhibited human monocyte cytotoxicity. When the role of different a-chains was studied, anti-alpha-L (CD11a, LFAI), anti-alpha-M (CD11b, Mac-I) and anti-alpha-X (CD11c, p150,95) caused marginal inhibition, but the effect of the 3 combined was comparable to that of anti-CD18. Anti-CD18 MAb did not affect the release of various cytotoxic molecules (e.g. TNF) by activated human monocytes. Activated monocytes showed augmented binding to target cells and anti-CD18 MAb inhibited the binding of resting and activated monocytes to tumor target cells. While IFN-gamma alone augmented expression of leukocyte integrins and LPS had no effect, the 2 activation signals, combined for optimal stimulation of tumoricidal activity, resulted in no appreciable increase in these leukocyte adhesion molecules, as assessed by flow cytometry. Our results suggest that the augmented CD18-dependent binding of activated monocytes on tumor cells depends mainly upon changes in the adhesive properties of these molecules rather than upon increased numbers on the cell surface. Anti-ICAM-I MAb significantly reduced monocyte cytotoxicity on tumor cells, which is consistent with a role of the CD11/CD18 adhesion pathway. These results implicate "activated" leukocyte (beta-2) integrins (CD11/CD18) as important adhesion molecules in the contact-dependent tumoricidal activity of human monocytes.