RRC ID 1335
Author Tajima K, Ito Y, Demachi A, Nishida K, Akatsuka Y, Tsujimura K, Hida T, Morishima Y, Kuwano H, Mitsudomi T, Takahashi T, Kuzushima K.
Title Interferon-gamma differentially regulates susceptibility of lung cancer cells to telomerase-specific cytotoxic T lymphocytes.
Journal Int. J. Cancer
Abstract There is accumulating evidence that peptides derived from the catalytic subunit of human telomerase reverse transcriptase (hTERT) are specifically recognized by CD8+ cytotoxic T lymphocytes. We investigated the cytotoxicity of a human leukocyte antigen (HLA)-A*2402-restricted hTERT-derived peptide 461-469 (hTERT461)-specific CD8+ T-cell clone, designated as K3-1, established from a healthy donor by repetitive peptide stimulation. This clone exhibited cytotoxicity against 4 out of 6 HLA-A24-positive lung cancer cell lines with positive telomerase activity but not 4 HLA-A24-negative examples. When the target cells were pretreated with 100 U/ml of interferon (IFN)-gamma for 48 hr, the susceptibility to K3-1 increased with PC9 cells but unexpectedly decreased with LU99 cells. However, in both cell lines, the expression of molecules associated with epitope presentation such as HLA-A24, transporters associated with antigen processing, low molecular weight polypeptide 7 and proteasome activator 28 was similarly increased after IFN-gamma treatment. Results of CTL assays using acid-extracted peptides indicated that the epitope increased on PC9 cells but not on LU99 cells after IFN-gamma treatment. Semi-quantitative reverse transcriptase polymerase chain reaction disclosed that the expression of hTERT was attenuated in LU99 but not in PC9 cells, accounting for the decreased cytotoxicity mediated by K3-1. The attenuation of the hTERT expression and K3-1-mediated cell lysis after IFN-gamma treatment was also observed in primary adenocarcinoma cells obtained from pulmonary fluid of a lung cancer patient. Our data underline the utility of peptide hTERT461 in immunotherapy for lung cancer, as with other malignancies reported earlier, and suggest that modulation of hTERT expression by IFN-gamma needs to be taken into account in therapeutic approach.
Volume 110(3)
Pages 403-12
Published 2004-6-20
DOI 10.1002/ijc.20139
PMID 15095306
MeSH Blotting, Western CD40 Antigens / biosynthesis CD8-Positive T-Lymphocytes / metabolism Cell Line, Tumor Cysteine Endopeptidases / metabolism DNA-Binding Proteins Dose-Response Relationship, Drug Down-Regulation Epitopes / chemistry Flow Cytometry Gene Expression Regulation, Neoplastic* HLA-A Antigens / chemistry Humans Immunotherapy Interferon-gamma / metabolism Interferon-gamma / physiology* Leukocytes, Mononuclear / metabolism Lung Neoplasms / metabolism* Lung Neoplasms / therapy* Multienzyme Complexes / metabolism Peptides / chemistry Proteasome Endopeptidase Complex Retroviridae / genetics Reverse Transcriptase Polymerase Chain Reaction T-Lymphocytes, Cytotoxic / metabolism* Telomerase / metabolism*
IF 4.982
Times Cited 17
Human and Animal Cells LC-1/sq