Lymphocyte-endothelial cell adhesion molecules at the primary tumor site in human lung and renal cell carcinomas.

The recruitment of lymphocytes from the blood is thought to be critical for the development of cellular responses to inflammation and neoplastic transformation (7,2). The adhesion of lymphocytes to endothelial cells that line blood vessel walls represents the first step in lymphocyte migration into the tissues {1-3). Various molecules have been reported (4,5) to mediate and direct lymphocyte-endothelial cell contacts; these molecules belong essentially to three distinct families: selectins, immunoglobulins, and integrins (4,5). We report here the distribution of such molecules on vascular endothelial cells and tumor-infiltrating lymphocytes at the sites of human lung adenocarcinomas (n = 8) and renal cell carcinomas (n = 8). The distribution was assessed by immunochemistry and immunofluorescence. The results of our study are summarized in Table 1. Both the cell-surface protein CD31 (6,7) and vascular cell adhesion molecule-1 (VCAM-1) (8) were strongly expressed on vascular endothelium at the tumor site in lung and renal cell carcinomas. The CD31 molecule, which has been reported to mediate homophilic interactions in endothelial cell-endothelial cell adhesion and in platelet-endothelial cell binding (7), was also detected on most rumorinfiltrating lymphocytes. Also, the integrin ot4 (CDw49d), which is one reported VCAM-1 ligand (8), was detected on more than one third of tumor-infiltrating lymphocytes. E-selectin (9) was detected in three of eight lung tumors and in four of eight renal cell carcinomas on blood vessels at the periphery of the tumor. E-selectin was only weakly expressed by microvascular endothelium in the proximity of the tumor cells. Sialylated Lewis x tetrasaccharide (CD15) antigen, which is one ligand for E-selectin (9), was expressed only by 5%-15% of isolated tumor-infiltrating lymphocytes and was undetectable in cryostat sections. We detected the intercellular adhesion molecule-1 (ICAM-1) (4) on endothelial cells in approximately two thirds of the tumors analyzed. We also found ICAM-1 in the stroma and on tumor cells as previously described by Tomita et al. (10). More than 95% of tumor-infiltrating lymphocytes were LFA-1 CDlla/CD18 positive, and about 65% expressed L-selectin (5). The L-selectin molecule has been shown to mediate tissue-selective interactions with "high" (as opposed to "flat") endothelial cells in venules in organized lymphoid tissues and with kidney glomerular endothelial cells in vitro (3,4,11). The differential expression of the various endothelial markers may depend on the secretion of inflammatory cytokines by leukocytes or by endothelial cel ls . Inflammatory cytokines include (a) tumor necrosis factor-a (TNF-a), which is reported to increase the expression of VCAM-1 and ICAM-1 molecules on endothelial cells and (b) interleukin-1 (IL-1), which induces E-selectin expression (1). We (12) have previously demonstrated that cloned tumorinfiltrating lymphocytes that express CD31 molecules were able to produce considerable amounts of TNF-a. Inflamed endothelium is thought to direct and regulate lymphocyte extravasation by the sequential expression of adhesion molecules in response to the inflammatory stimulus