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Lymphocyte‐facilitated tumour cell adhesion to endothelial cells: the role of high affinity leucocyte integrins

Aim: Lymphocytes transiently express an active form of the β_2 integrin LFA‐1 (LFA‐1Af) which has conformational changes in extracellular domains enabling higher affinity binding to the ligand ICAM‐1. In this study, we investigated the role of lymphocytes bearing LFA‐1Af as potential mediators of binding of ICAM‐1‐positive tumour cells to endothelium. Methods: LFA‐1 expression on 51Cr‐PBLs was modulated in order to express high affinity LFA‐1Af and conjugates were formed with 35S‐labelled COLO526. The binding of the conjugates to resting or IL‐1β‐stimulated human umbilical vein endothelial cells (HUVECs) was then assessed via a modified radioactive HUVEC binding assay. In addition, the binding of PBL‐COLO526 conjugates to HUVECs was demonstrated by confocal microscopy. Results: The binding of COLO526 to endothelial cells did not change significantly between unstimulated and stimulated HUVECs. In addition, pre‐incubating the COLO526 with fresh PBLs did not significantly alter the binding of COLO526 to resting or activated HUVECs; whereas, in the presence of PBLs with LFA‐1Af, the COLO526 conjugate binding dramatically increased from basal levels to 41% on resting HUVECs and 81% on stimulated HUVECs. COLO526‐PBL(LFA‐1Af) conjugate adhesion to stimulated HUVECs was inhibited by blocking antibody to LFA‐1 (50%), VLA‐4 (32%) or L‐selectin (40%). Antibodies to the HUVEC adhesion molecules ICAM‐1, VCAM‐1 and E‐selectin also inhibited COLO526‐PBL(LFA‐1Af) conjugate binding to activated HUVECs by 79, 60 and 73%, respectively. Conclusions: PBLs bearing LFA‐1Af can enhance COLO526 adhesion to both resting and activated HUVECs. Furthermore, blocking studies demonstrate that a range of pathways are involved in this phenomenon (LFA‐1/ICAM‐1, VLA4/VCAM‐1, L‐selectin/E‐selectin). These studies have identified a novel alternative pathway for lymphocyte‐facilitated tumour cell adhesion to endothelial cells.