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

被引:252
作者
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
机构
[1] Natl Inst Canc Res, Lab Translat Res A, I-16132 Genoa, Italy
[2] Univ Genoa, DOBIG, Genoa, Italy
[3] Univ Genoa, Dept Biol, Genoa, Italy
[4] St Orsola Marcello Malpighi Hosp, Serv Transfus Med, Bologna, Italy
[5] Univ Bologna, Dept Human Anat Sci, Bologna, Italy
[6] Natl Inst Canc Res, Lab Immunopharmacol, I-16132 Genoa, Italy
[7] Natl Inst Canc Res, Lab Anat Pathol, I-16132 Genoa, Italy
[8] St Marianna Univ, Dept Bioregulat, Inst Med Sci, Sch Med, Kanagawa, Japan
[9] Dept Surg Pathol, Bologna, Italy
[10] Ist Ortoped Rizzoli, Regenerat & Tissue Engn Lab, Bologna, Italy
[11] Univ Bologna, Dept Expt Pathol, I-40126 Bologna, Italy
[12] CNR, ITB, Dulbecco Telethon Inst, I-20133 Milan, Italy
关键词
CTLA-4; tumors; ligands; apoptosis;
D O I
10.1002/ijc.21155
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 apoplosis 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. (c) 2005 Wiley-Liss, Inc.
引用
收藏
页码:538 / 550
页数:13
相关论文
共 53 条
  • [21] The CTLA-4 gene is expressed in placental fibroblasts
    Kaufman, KA
    Bowen, JA
    Tsai, AF
    Bluestone, JA
    Hunt, JS
    Ober, C
    [J]. MOLECULAR HUMAN REPRODUCTION, 1999, 5 (01) : 84 - 87
  • [22] CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells
    Krummel, MF
    Allison, JP
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 183 (06) : 2533 - 2540
  • [23] Enhancement of antitumor immunity by CTLA-4 blockade
    Leach, DR
    Krummel, MF
    Allison, JP
    [J]. SCIENCE, 1996, 271 (5256) : 1734 - 1736
  • [24] Human CD25+ CD4+ T suppressor cell clones produce transforming growth factor β, but not interleukin 10, and are distinct from type 1 T regulatory cells
    Levings, MK
    Sangregorio, R
    Sartirana, C
    Moschin, AL
    Battaglia, M
    Orban, PC
    Roncarolo, MG
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2002, 196 (10) : 1335 - 1346
  • [25] HUMAN B7-1 (CD80) AND B7-2 (CD86) BIND WITH SIMILAR AVIDITIES BUT DISTINCT KINETICS TO CD28 AND CTLA-4 RECEPTORS
    LINSLEY, PS
    GREENE, JL
    BRADY, W
    BAJORATH, J
    LEDBETTER, JA
    PEACH, R
    [J]. IMMUNITY, 1994, 1 (09) : 793 - 801
  • [26] Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement
    Linsley, PS
    Bradshaw, J
    Greene, J
    Peach, R
    Bennett, KL
    Mittler, RS
    [J]. IMMUNITY, 1996, 4 (06) : 535 - 543
  • [27] Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma
    Liyanage, UK
    Moore, TT
    Joo, HG
    Tanaka, Y
    Herrmann, V
    Doherty, G
    Drebin, JA
    Strasberg, SM
    Eberlein, TJ
    Goedegebuure, PS
    Linehan, DC
    [J]. JOURNAL OF IMMUNOLOGY, 2002, 169 (05) : 2756 - 2761
  • [28] Magistrelli G, 1999, EUR J IMMUNOL, V29, P3596, DOI 10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.3.CO
  • [29] 2-P
  • [30] Martelli AM, 2004, HAEMATOLOGICA, V89, P471