Tumor-infiltrating CD4+ T lymphocytes express APO2 ligand (APO2L)/TRAIL upon specific stimulation with autologous lung carcinoma cells: role of IFN-alpha on APO2L/TRAIL expression and -mediated cytotoxicity.
In the present report, we have investigated TRAIL/APO2 ligand (APO2L) expression, regulation, and function in human lung carcinoma tumor-infiltrating lymphocytes. Using a panel of non-small cell lung carcinoma cell lines, we first showed that most of them expressed TRAIL-R1/DR4, TRAIL-R2/DR5, but not TRAIL-R3/DcR1 and TRAIL-R4/DcR2, and were susceptible to APO2L/TRAIL-induced cell death. Two APO2L/TRAIL-sensitive tumor cell lines (MHC class I(+)/II(+) or I(+)/II(-)) were selected and specific CD4(+) HLA-DR- or CD8(+) HLA-A2-restricted CTL clones were respectively isolated from autologous tumor-infiltrating lymphocytes. Interestingly, although the established T cell clones did not constitutively express detectable levels of APO2L/TRAIL, engagement of their TCR via activation with specific tumor cells selectively induced profound APO2L/TRAIL expression on the CD4(+), but not on the CD8(+), CTL clones. Furthermore, as opposed to the CD8(+) CTL clone which mainly used granule exocytosis pathway, the CD4(+) CTL clone lysed the specific target via both perforin/granzymes and APO2L/TRAIL-mediated mechanisms. The latter cytotoxicity correlated with APO2L/TRAIL expression and was significantly enhanced in the presence of IFN-alpha. More interestingly, in vivo studies performed in SCID/nonobese diabetic mice transplanted with autologous tumor and transferred with the specific CD4(+) CTL clone in combination with IFN-alpha resulted in an important APO2L/TRAIL-mediated tumor growth inhibition, which was prohibited by soluble TRAIL-R2. Our findings suggest that APO2L/TRAIL, specifically induced by autologous tumor and up-regulated by IFN-alpha, may be a key mediator of tumor-specific CD4(+) CTL-mediated cell death and point to a potent role of this T cell subset in tumor growth control.
Dorothée
Guillaume
G
Laboratoire Cytokines et Immunologie des Tumeurs Humaines, Institut National de la Santé et de la Recherche Médicale Unité 487, Institut Gustave Roussy, Villejuif, France.
Vergnon
Isabelle
I
Menez
Jeanne
J
Echchakir
Hamid
H
Grunenwald
Dominique
D
Kubin
Marek
M
Chouaib
Salem
S
Mami-Chouaib
Fathia
F
D019264:Adoptive Transfer; D000368:Aged; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D006801:Humans; D015552:Injections, Intralesional; D016898:Interferon-alpha / Q000008:administration & dosage / Q000502:physiology* / Q000633:toxicity; D008024:Ligands; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000502:physiology / Q000633:toxicity*; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000502:physiology / Q000633:toxicity*
D051017:Apoptosis Regulatory Proteins; D006131:Growth Inhibitors; D016898:Interferon-alpha; D008024:Ligands; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha