Role for CD40-CD40 ligand interactions in the immune response to solid tumours.
CD40-mediated interactions play an important role in the response to infections, transplantation, and cancer by affecting the development, activation, proliferation and differentiation of a variety of immune cells. In the current study we examined the role of CD40-mediated interactions in immune responses to bladder, pancreatic and breast carcinomas as well as melanoma cell 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 and was augmented but not induced de novo by treatment with IFNgamma. Treatment 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, GROalpha, GM-CSF and TNFalpha but not IL-4, IL-10, TGFbeta, MCP-1, RANTES, MIP-1beta, or IP-10. In addition, incubation of CD40+ tumour cell lines with immobilised rhCD40L or anti-CD40 mAb in vitro resulted in significant inhibition of proliferation and a corresponding decrease in viability. 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 responsiveness to rhCD40L and anti-CD40 antibody. Finally, the presence of CD40 on the surface of carcinoma lines was found to be an important factor in the generation of tumour-specific T cell responses.
Alexandroff
A B
AB
Department of Clinical and Surgical Sciences, Edinburgh University, Lister Laboratories, Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW, UK.
Jackson
A M
AM
Paterson
T
T
Haley
J L
JL
Ross
J A
JA
Longo
D L
DL
Murphy
W J
WJ
James
K
K
Taub
D D
DD
D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology*; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002453:Cell Cycle; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D053222:Fas Ligand Protein; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D007519:Isoantigens / Q000276:immunology; D020014:K562 Cells; D008545:Melanoma / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D010190:Pancreatic Neoplasms / Q000276:immunology*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007519:Isoantigens; D008562:Membrane Glycoproteins; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; D007371:Interferon-gamma