title: CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction.
abstract: CTLA-4 (CD152) is a cell surface receptor that behaves as a negative regulator of the proliferation and the effector function of T cells. We have previously shown that CTLA-4 is also expressed on neoplastic lymphoid and myeloid cells, and it can be targeted to induce apoptosis. In our study, we have extended our analysis and have discovered that surface expression of CTLA-4 is detectable by flow cytometry on 30 of 34 (88%) cell lines derived from a variety of human malignant solid tumors including carcinoma, melanoma, neuroblastoma, rhabdomyosarcoma and osteosarcoma (but not in primary osteoblast-like cultures). However, by reverse transcriptase-PCR, CTLA-4 expression was detected in all cell lines. We have also found, by immunohistochemistry, cytoplasmic and surface expression of CTLA-4 in the tumor cells of all 6 osteosarcoma specimens examined and in the tumour cells of all 5 cases (but only weakly or no positivity at all in neighbouring nontumor cells) of ductal breast carcinomas. Treatment of cells from CTLA-4-expressing tumor lines with recombinant forms of the CTLA-4-ligands CD80 and CD86 induced apoptosis associated with sequential activation of caspase-8 and caspase-3. The level of apoptosis was reduced by soluble CTLA-4 and by anti-CTLA-4 scFvs antibodies. The novel finding that CTLA-4 molecule is expressed and functional on human tumor cells opens up the possibility of antitumor therapeutic intervention based on targeting this molecule.
authors.affiliation: Department of Oncology, Biology and Genetics (DOBIG), University of Genova, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Contardi
authors.forename: Giulio L
authors.initials: GL
authors.lastname: Palmisano
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Tazzari
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.forename: Federica
authors.initials: F
authors.lastname: Falà
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kato
authors.forename: Enrico
authors.initials: E
authors.lastname: Lucarelli
authors.forename: Davide
authors.initials: D
authors.lastname: Donati
authors.forename: Letizia
authors.initials: L
authors.lastname: Polito
authors.forename: Andrea
authors.initials: A
authors.lastname: Bolognesi
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.forename: Sandra
authors.initials: S
authors.lastname: Salvi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Gargaglione
authors.forename: Stefano
authors.initials: S
authors.lastname: Mantero
authors.forename: Marco
authors.initials: M
authors.lastname: Alberghini
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ferrara
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Pistillo
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism* / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D060908:CTLA-4 Antigen; D045744:Cell Line, Tumor; D017931:DNA Primers; D018076:DNA, Complementary; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D017931:DNA Primers; D018076:DNA, Complementary; D008024:Ligands