There is growing evidence suggesting that the sequence of adhesive events which occurs normally between circulating leukocytes and endothelial cells during an inflammatory response is defective with in tumors. There is deficient expression of adhesion molecules that are normally induced on cytokine- activated endothelial cells both in human neoplasms and in murine tumor models. Several angiogenic factors (e.g., bFGF and VEGF) and cytokines (e.g., TGF-beta, IL-4) have been shown to suppress expression of induced (e.g., VCAM-1, E-selectins) and constitutively expressed (e.g., ICAM-1) endothelial adhesion molecules in vitro. The expression of endothelial adhesion molecules that are requisite for the transendothelial migration of NK cells in vitro will be characterized pre-and post-adoptive immunotherapy with A (adherent)-NK cells and IL-2 in 3 syngeneic murine tumor models (B16 melanoma, 3LL lung carcinoma, MCA102 fibrosarcoma). The cytokines which positively (e.g., IL-1, TNF-alpha, IFN-gamma) and negatively (e.g., TGF-beta, IL-4, IL-10) regulate the expression of these adhesion molecules will be examined by immunofluorescent microscopy and in situ hybridization techniques. The migration of subsets of A-NK cells expressing different combinations of leukocyte adhesion molecules into local tumors or experimental liver or lung metastases will be monitored using A-NK cells from congenic strain of C57B1/6 mice. The importance of the adhesion molecules during recruitment of A-NK cells at the three sites also will be demonstrated by administering monoclonal antibodies that block the adhesive function of these molecules and by using C57B1/6 mice deficient in the expression of endothelia adhesion molecules (e.g., ICAM-1, P-selectin). The adhesion molecules both on the endothelium within local tumors and on the A-NK cells will be modulated to increase A-NK cell binding to tumor endothelium. Finally, the therapeutic efficacy of increased recruitment of A-NK cells will be determined in tumor-bearing animals. Increasing adhesive interactions between adoptively transferred leukocytes or endogenous leukocytes activated by the administration of cytokines offers a novel approach to improve the therapeutic efficacy of adoptive immunotherapy.
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