CD40-CD40 ligand (CD154) engagement is required but not sufficient for modulating MHC class I, ICAM-1 and Fas expression and proliferation of human non-small cell lung tumors

To determine the possible functional significance of CD40 expression on hum an non-small cell lung carcinomas and to assess the potential of CD40 as a therapeutic target, 18 lung tumor cell lines were established from biopsy t issues and were monitored for phenotypic changes on the cell surface and al terations in tumor cell proliferation after the ligation of CD40 with a tri meric fusion protein complex of CD40 ligand (CD40Lt). CD40 cross-linking re sulted in up to a 6-fold increase in the surface expression of major histoc ompatibility complex (MHC) class I, Fas and intracellular adhesion mole cut e (ICAM)-I in a subset of tumors expressing the highest levels of CD40, Sup pression of tumor proliferation was seen after the ligation of CD40 on CD40 Lt-responsive cell lines. The suppression was dose dependent, reversible an d resulted from a delay of the tumor cells entering S-phase, No change in t he cell phenotype or in proliferation were observed in CD40-negative tumors or in tumors expressing moderate-to-low levels of CD40 after incubation wi th CD40Lt. CD40-negative tumors transfected with the CD40 gene expressed hi gh levels of CD40 on their surface, but were also unresponsive to CD40Lt cr oss linking of CD40, Our data establish that CD40 is required (but not suff icient) for transducing a signal that results in phenotypic changes in huma n lung tumors and suppression in their proliferation. We conclude that CD40 on non-small cell lung tumors may represent a potential therapeutic target , but only on a subset of the CD40+ tumors. (C) 2001 Wiley-Liss, Inc.