The LFA‐1/ICAM cell adhesion pathway is involved in tumor‐cell lysis mediated by bispecific monoclonal‐antibody‐targeted T lymphocytes

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Abstract
We investigated the role of the LFA‐1 /ICAM, VLA‐4/VCAM‐1 and CD2/LFA‐3 adhesion pathways in the cytolysis of tumor cells mediated by an anti‐EGF‐R/anti‐CD3 bispecific monoclonal antibody (biMAb). The biMAb induced efficient lysis of EGF‐R+ tumor cells (A431, HT‐29, IGROV‐1 and MDA‐MB468) by cytotoxic T lymphocytes (CTL) cultured in IL‐2. Protreatment of effector cells by anti‐LFA‐1α (CDI 1a) and anti‐LFA‐1 β (CD 18) MAbs significantly inhibited cytolysis of all types of EGF‐R+ tumor cells, while anti‐CD2 and anti‐VLA‐4 MAbs were virtually ineffective. We investigated the expression of adhesion‐molecule counter‐receptors on tumor target cells by indirect immunofluorescence. HT‐29, A431 and MDA‐MB 468 tumor cells expressed an ICAM‐1+2−3−VCAM‐1−LFA‐3+ phenotype, while IGROV‐1 was ICAM‐1−2+3−VCAM‐1 −LFA‐3+. Pre‐treatment of A431, HT‐29 and MDA‐MB468 with anti‐ICAM‐1 MAb inhibited cytolysis, further supporting the functional involvement of the LFA‐1 /ICAM adhesion pathway in biMAb‐targeted tumor‐cell lysis. In addition, treatment of target cells with TNFα or IFN‐γ for 24 hr increased the expression of ICAM‐1 in HT‐29, A431 and MDA‐MB468 (ICAM‐2 was induced on IGROV‐1) and also enhanced the sensitivity of these target cells to biMAb‐targeted cytotoxicity. These data suggest that up‐regulation of ICAM‐molecule expression by inflammatory cytokines may increase susceptibility of tumor cells to biMAb‐targeted lysis. Anti‐LFA‐1 MAbs did not significantly inhibit the formation of conjugates between biMAb‐coated T lymphocytes and tumor cells. Co‐aggregation of LFA‐1 molecules with biMAb‐bound CD3 molecules resulted in a more sustained and prolonged increase in the intracellular concentration of. free Ca++ in CD8+ cultured CTL lines. These findings indicate that in T cells targeted by anti‐CD3/anti‐TAA biMAb LFA‐1 may act as a co‐receptor molecule which enhances signal transduction through the CD3/TCR complex.

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