CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction

Elisabetta Contardi, Giulio L. Palmisano, Pier Luigi Tazzari, Alberto M. Martelli, Federica Falà, Marina Fabbi, Tomohiro Kato, Enrico Lucarelli, Davide Donati, Letizia Polito, Andrea Bolognesi, Francesca Ricci, Sandra Salvi, Vittoria Gargaglione, Stefano Mantero, Marco Alberghini, Giovanni Battista Ferrara, Maria Pia Pistillo

Research output: Contribution to journalArticle

138 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)538-550
Number of pages13
JournalInternational Journal of Cancer
Volume117
Issue number4
DOIs
Publication statusPublished - Nov 20 2005

Fingerprint

Apoptosis
Ligands
Osteosarcoma
Neoplasms
Carcinoma, Ductal, Breast
Cell Line
Rhabdomyosarcoma
Caspase 8
Cell Surface Receptors
Myeloid Cells
Reverse Transcriptase Polymerase Chain Reaction
Osteoblasts
Neuroblastoma
Caspase 3
Melanoma
Flow Cytometry
Immunohistochemistry
Lymphocytes
Carcinoma
T-Lymphocytes

Keywords

  • Apoptosis
  • CTLA-4
  • Ligands
  • Tumors

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction. / Contardi, Elisabetta; Palmisano, Giulio L.; Tazzari, Pier Luigi; Martelli, Alberto M.; Falà, Federica; Fabbi, Marina; Kato, Tomohiro; Lucarelli, Enrico; Donati, Davide; Polito, Letizia; Bolognesi, Andrea; Ricci, Francesca; Salvi, Sandra; Gargaglione, Vittoria; Mantero, Stefano; Alberghini, Marco; Ferrara, Giovanni Battista; Pistillo, Maria Pia.

In: International Journal of Cancer, Vol. 117, No. 4, 20.11.2005, p. 538-550.

Research output: Contribution to journalArticle

Contardi, E, Palmisano, GL, Tazzari, PL, Martelli, AM, Falà, F, Fabbi, M, Kato, T, Lucarelli, E, Donati, D, Polito, L, Bolognesi, A, Ricci, F, Salvi, S, Gargaglione, V, Mantero, S, Alberghini, M, Ferrara, GB & Pistillo, MP 2005, 'CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction', International Journal of Cancer, vol. 117, no. 4, pp. 538-550. https://doi.org/10.1002/ijc.21155
Contardi, Elisabetta ; Palmisano, Giulio L. ; Tazzari, Pier Luigi ; Martelli, Alberto M. ; Falà, Federica ; Fabbi, Marina ; Kato, Tomohiro ; Lucarelli, Enrico ; Donati, Davide ; Polito, Letizia ; Bolognesi, Andrea ; Ricci, Francesca ; Salvi, Sandra ; Gargaglione, Vittoria ; Mantero, Stefano ; Alberghini, Marco ; Ferrara, Giovanni Battista ; Pistillo, Maria Pia. / CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction. In: International Journal of Cancer. 2005 ; Vol. 117, No. 4. pp. 538-550.
@article{924a765818254d32b3abb93f3aa2f343,
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.",
keywords = "Apoptosis, CTLA-4, Ligands, Tumors",
author = "Elisabetta Contardi and Palmisano, {Giulio L.} and Tazzari, {Pier Luigi} and Martelli, {Alberto M.} and Federica Fal{\`a} and Marina Fabbi and Tomohiro Kato and Enrico Lucarelli and Davide Donati and Letizia Polito and Andrea Bolognesi and Francesca Ricci and Sandra Salvi and Vittoria Gargaglione and Stefano Mantero and Marco Alberghini and Ferrara, {Giovanni Battista} and Pistillo, {Maria Pia}",
year = "2005",
month = "11",
day = "20",
doi = "10.1002/ijc.21155",
language = "English",
volume = "117",
pages = "538--550",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction

AU - Contardi, Elisabetta

AU - Palmisano, Giulio L.

AU - Tazzari, Pier Luigi

AU - Martelli, Alberto M.

AU - Falà, Federica

AU - Fabbi, Marina

AU - Kato, Tomohiro

AU - Lucarelli, Enrico

AU - Donati, Davide

AU - Polito, Letizia

AU - Bolognesi, Andrea

AU - Ricci, Francesca

AU - Salvi, Sandra

AU - Gargaglione, Vittoria

AU - Mantero, Stefano

AU - Alberghini, Marco

AU - Ferrara, Giovanni Battista

AU - Pistillo, Maria Pia

PY - 2005/11/20

Y1 - 2005/11/20

N2 - 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.

AB - 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.

KW - Apoptosis

KW - CTLA-4

KW - Ligands

KW - Tumors

UR - http://www.scopus.com/inward/record.url?scp=27144458821&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27144458821&partnerID=8YFLogxK

U2 - 10.1002/ijc.21155

DO - 10.1002/ijc.21155

M3 - Article

C2 - 15912538

AN - SCOPUS:27144458821

VL - 117

SP - 538

EP - 550

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 4

ER -