THE LFA-1/ICAM CELL-ADHESION PATHWAY IS INVOLVED IN TUMOR-CELL LYSIS MEDIATED BY BISPECIFIC MONOCLONAL-ANTIBODY-TARGETED T-LYMPHOCYTES

被引:31
作者
FERRINI, S [1 ]
SFORZINI, S [1 ]
CAMBIAGGI, A [1 ]
POGGI, A [1 ]
MEAZZA, R [1 ]
CANEVARI, S [1 ]
COLNAGHI, MI [1 ]
MORETTA, L [1 ]
机构
[1] IST NAZL TUMORI, I-20133 MILAN, ITALY
关键词
D O I
10.1002/ijc.2910560616
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. Pre-treatment of effector cells by anti-LFA-1 alpha (CDIIa) and anti-LFA-1 beta (CD18) 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 TNF alpha or IFN gamma 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. (C) 1994 Wiley-Liss, Inc.
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页码:846 / 852
页数:7
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