Interferon-γ differentially regulates susceptibility of lung cancer cells to telomerase-specific cytotoxic T lymphocytes

Kouhei Tajima, Yoshinori Ito, Ayako Demachi, Keiko Nishida, Yoshiki Akatsuka, Kunio Tsujimura, Toyoaki Hida, Yasuo Morishima, Hiroyuki Kuwano, Tetsuya Mitsudomi, Toshitada Takahashi, Kiyotaka Kuzushima

Research output: Contribution to journalArticle

24 Citations (Scopus)

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)-γ 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-γ treatment. Results of CTL assays using acid-extracted peptides indicated that the epitope increased on PC9 cells but not on LU99 cells after IFN-γ 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-γ 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-γ needs to be taken into account in therapeutic approach.

Original languageEnglish
Pages (from-to)403-412
Number of pages10
JournalInternational Journal of Cancer
Volume110
Issue number3
DOIs
Publication statusPublished - 20-06-2004

Fingerprint

Telomerase
Cytotoxic T-Lymphocytes
Interferons
Lung Neoplasms
Peptides
HLA Antigens
Epitopes
Clone Cells
Cell Line
Antigen Presentation
Proteasome Endopeptidase Complex
Therapeutics
Reverse Transcriptase Polymerase Chain Reaction
Immunotherapy
Catalytic Domain
Adenocarcinoma
Molecular Weight
human TERT protein
Tissue Donors
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Tajima, Kouhei ; Ito, Yoshinori ; Demachi, Ayako ; Nishida, Keiko ; Akatsuka, Yoshiki ; Tsujimura, Kunio ; Hida, Toyoaki ; Morishima, Yasuo ; Kuwano, Hiroyuki ; Mitsudomi, Tetsuya ; Takahashi, Toshitada ; Kuzushima, Kiyotaka. / Interferon-γ differentially regulates susceptibility of lung cancer cells to telomerase-specific cytotoxic T lymphocytes. In: International Journal of Cancer. 2004 ; Vol. 110, No. 3. pp. 403-412.
@article{1b0779007c014201885b451ca304ec5f,
title = "Interferon-γ differentially regulates susceptibility of lung cancer cells to telomerase-specific cytotoxic T lymphocytes",
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)-γ 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-γ treatment. Results of CTL assays using acid-extracted peptides indicated that the epitope increased on PC9 cells but not on LU99 cells after IFN-γ 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-γ 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-γ needs to be taken into account in therapeutic approach.",
author = "Kouhei Tajima and Yoshinori Ito and Ayako Demachi and Keiko Nishida and Yoshiki Akatsuka and Kunio Tsujimura and Toyoaki Hida and Yasuo Morishima and Hiroyuki Kuwano and Tetsuya Mitsudomi and Toshitada Takahashi and Kiyotaka Kuzushima",
year = "2004",
month = "6",
day = "20",
doi = "10.1002/ijc.20139",
language = "English",
volume = "110",
pages = "403--412",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "3",

}

Tajima, K, Ito, Y, Demachi, A, Nishida, K, Akatsuka, Y, Tsujimura, K, Hida, T, Morishima, Y, Kuwano, H, Mitsudomi, T, Takahashi, T & Kuzushima, K 2004, 'Interferon-γ differentially regulates susceptibility of lung cancer cells to telomerase-specific cytotoxic T lymphocytes', International Journal of Cancer, vol. 110, no. 3, pp. 403-412. https://doi.org/10.1002/ijc.20139

Interferon-γ differentially regulates susceptibility of lung cancer cells to telomerase-specific cytotoxic T lymphocytes. / Tajima, Kouhei; Ito, Yoshinori; Demachi, Ayako; Nishida, Keiko; Akatsuka, Yoshiki; Tsujimura, Kunio; Hida, Toyoaki; Morishima, Yasuo; Kuwano, Hiroyuki; Mitsudomi, Tetsuya; Takahashi, Toshitada; Kuzushima, Kiyotaka.

In: International Journal of Cancer, Vol. 110, No. 3, 20.06.2004, p. 403-412.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Interferon-γ differentially regulates susceptibility of lung cancer cells to telomerase-specific cytotoxic T lymphocytes

AU - Tajima, Kouhei

AU - Ito, Yoshinori

AU - Demachi, Ayako

AU - Nishida, Keiko

AU - Akatsuka, Yoshiki

AU - Tsujimura, Kunio

AU - Hida, Toyoaki

AU - Morishima, Yasuo

AU - Kuwano, Hiroyuki

AU - Mitsudomi, Tetsuya

AU - Takahashi, Toshitada

AU - Kuzushima, Kiyotaka

PY - 2004/6/20

Y1 - 2004/6/20

N2 - 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)-γ 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-γ treatment. Results of CTL assays using acid-extracted peptides indicated that the epitope increased on PC9 cells but not on LU99 cells after IFN-γ 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-γ 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-γ needs to be taken into account in therapeutic approach.

AB - 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)-γ 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-γ treatment. Results of CTL assays using acid-extracted peptides indicated that the epitope increased on PC9 cells but not on LU99 cells after IFN-γ 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-γ 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-γ needs to be taken into account in therapeutic approach.

UR - http://www.scopus.com/inward/record.url?scp=2442455516&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2442455516&partnerID=8YFLogxK

U2 - 10.1002/ijc.20139

DO - 10.1002/ijc.20139

M3 - Article

C2 - 15095306

AN - SCOPUS:2442455516

VL - 110

SP - 403

EP - 412

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 3

ER -