title: CD40 activation of carcinoma cells increases expression of adhesion and major histocompatibility molecules but fails to induce either CD80/CD86 expression or T cell alloreactivity.
abstract: A major obstacle for the development of cancer immunotherapy is the poor capacity of most tumor cells to present antigen. It has previously been shown that ligation of CD40 on the surface of malignant B cells results in the induction of efficient antigen presentation primarily because of upregulated expression of MHC, costimulatory, and adhesion molecules. Ongoing clinical trials are testing the impact of CD40 ligation as immunotherapy for B cell malignancies. Because CD40 is also widely expressed in carcinomas, we studied whether CD40 activation of these cells using soluble recombinant trimeric human CD40 ligand (srhCD40L) can also induce T cell responses. Here, we show that carcinoma cells upregulate expression of CD54 and MHC molecules following in vitro exposure to srhCD40L but do not upregulate CD80 or CD86. CD40-activated carcinoma cells failed to trigger mixed lymphocyte reactions, in sharp contrast to CD40-activated lymphoma cells for which CD40 activation, as expected, resulted in increased expression of MHC, adhesion, and costimulatory molecules, and generated brisk allogeneic lymphocyte reactions. Retroviral-mediated expression of CD80 in carcinoma cells, with or without CD40 activation, triggered mixed lymphocyte reactions, provided cells were treated with IFN-gamma. Thus, the cell surface phenotype induced on carcinoma cells following CD40 activation is not fully capable of inducing T cell proliferation; however, these results support ongoing efforts to exploit costimulation in clinical efforts aimed at increasing carcinoma immunogenicity.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. robert_vonderheide@dfci.harvard.edu
authors.forename: R H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: M O
authors.initials: MO
authors.lastname: Butler
authors.forename: J F
authors.initials: JF
authors.lastname: Liu
authors.forename: T E
authors.initials: TE
authors.lastname: Battle
authors.forename: N
authors.initials: N
authors.lastname: Hirano
authors.forename: J G
authors.initials: JG
authors.lastname: Gribben
authors.forename: D A
authors.initials: DA
authors.lastname: Frank
authors.forename: J L
authors.initials: JL
authors.lastname: Schultze
authors.forename: L M
authors.initials: LM
authors.lastname: Nadler
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism*; D051940:B7-2 Antigen; D015153:Blotting, Western; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D008562:Membrane Glycoproteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D015815:Cell Adhesion Molecules; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases