Role for CD40-CD40 ligand interactions in the immune response to solid tumours

CD40-mediated interactions play an important role in the response to infect ions, transplantation, and cancer by affecting the development, activation, proliferation and differentiation of a variety of immune cells. In the cur rent study we examined the role of CD40-mediated interactions in immune res ponses to bladder, pancreatic and breast carcinomas as well as melanoma cel l lines using soluble human CD40L (rhCD40L) or anti-CD40 mAb in vitro. CD40 expression was readily detected in a large proportion of the cell lines an d was augmented but not induced de novo by treatment with IFN gamma. Treatm ent of CD40-positive cell lines with rhCD40L or anti-CD40mAb enhanced cell surface expression of ICAM-1 and FAS and stimulated the production of IL-6, IL-8, GRO alpha, GM-CSF and TNF alpha but not IL-4, IL-10, TGF beta, MCP-1 , RANTES, MIP-1 beta, or IP-10. In addition, incubation of CD40 + tumour ce ll lines with immobilised rhCD40L or anti-CD40 mAb in vitro resulted in sig nificant inhibition of proliferation and a corresponding decrease in viabil ity. This CD40-mediated inhibition of cell growth was due, at least in part , to alterations in cell cycle and the induction of apoptosis. Transfection of CD40-negative tumour cell lines with the cDNA for CD40 conferred respon siveness to rhCD40L and anti-CD40 antibody. Finally, the presence of CD40 o n the surface of carcinoma lines was found to be an important factor in the generation of tumour-specific T cell responses. (C) 2000 Elsevier Science Ltd. All rights reserved.