Abstract |
Renal cell carcinoma-infiltrating lymphocytes express killer cell immunoglobulin-like receptors (KIRs) that inhibit antitumor CD8+ T-cell functions and may contribute to local self-tolerance. In the present study, to better examine the functional consequences of KIR engagement on CTL- tumor interactions, we investigated the influence of KIR2DL1/CD158a on CTL survival. We show that both KIR+ and KIR- antigen-specific CTLs express Fas and Fas ligand and were susceptible to activation-induced cell death (AICD) triggered by coated anti-CD3 monoclonal antibodies. In KIR+ CTLs, anti-CD158a monoclonal antibodies partially inhibited anti-CD3-induced AICD. Interestingly, T-cell receptor activation by cognate tumor cells induced apoptosis in KIR+ CTLs but not in KIR- CTLs. In addition, co-engagement of T-cell receptors and KIRs by tumor cells decreased tumor-mediated CTL apoptosis. Blocking the interaction of KIR/ HLA-Cw4 resulted in the restoration of tumor-induced AICD. Most importantly, our data indicate that KIR engagement affected two proximal events of Fas signaling pathway, a sustained c- FLIP-L induction and a decrease in caspase 8 activity. These studies provide evidence that tumor cells selectively favor the local persistence of nonfunctional KIR+ CTLs by promoting their survival.
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Authors | Asma Gati, Nadia Guerra, Catherine Gaudin, Sylvie Da Rocha, Bernard Escudier, Yann Lécluse, Ali Bettaieb, Salem Chouaib, Anne Caignard |
Journal | Cancer research
(Cancer Res)
Vol. 63
Issue 21
Pg. 7475-82
(Nov 01 2003)
ISSN: 0008-5472 [Print] United States |
PMID | 14612548
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- CD3 Complex
- Receptors, Immunologic
- Receptors, KIR
- Receptors, KIR2DL1
- fas Receptor
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Topics |
- Antibodies, Monoclonal
(immunology)
- Antibody Specificity
- CD3 Complex
(immunology)
- Carcinoma, Renal Cell
(immunology)
- Cell Death
(immunology)
- Down-Regulation
- Humans
- Kidney Neoplasms
(immunology)
- Lymphocyte Activation
- Receptors, Immunologic
(immunology)
- Receptors, KIR
- Receptors, KIR2DL1
- Signal Transduction
(immunology)
- T-Lymphocytes, Cytotoxic
(immunology)
- Tumor Cells, Cultured
- fas Receptor
(immunology)
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