Role of leukotriene B4 12-hydroxydehydrogenase in α-galactosylceramide-pulsed dendritic cell therapy for non-small cell lung cancer

Kazuhisa Tanaka; Yuri Kanesaka; Mariko Takami; Akane Suzuki; Hiroyuki Hosokawa; Atsushi Onodera; Toshiko Kamata; Kaoru Nagato; Toshinori Nakayama; Ichiro Yoshino; Shinichiro Motohashi

doi:10.1016/j.bbrc.2018.10.048

Role of leukotriene B4 12-hydroxydehydrogenase in α-galactosylceramide-pulsed dendritic cell therapy for non-small cell lung cancer

Biochem Biophys Res Commun. 2018 Nov 17;506(1):27-32. doi: 10.1016/j.bbrc.2018.10.048. Epub 2018 Oct 15.

Affiliations

¹ Department of Medical Immunology, Graduate School of Medicine, Chiba University, 2608670, Chiba, Japan; Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, 2608670, Chiba, Japan.
² Department of Medical Immunology, Graduate School of Medicine, Chiba University, 2608670, Chiba, Japan.
³ Department of Immunology, Graduate School of Medicine, Chiba University, 2608670, Chiba, Japan.
⁴ Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, 2608670, Chiba, Japan.
⁵ Department of Medical Immunology, Graduate School of Medicine, Chiba University, 2608670, Chiba, Japan. Electronic address: [email protected].

PMID: 30336981
DOI: 10.1016/j.bbrc.2018.10.048

Abstract

Invariant natural killer T (iNKT) cells exhibit potent antitumor effects upon activation by recognizing a specific glycolipid antigen. We previously performed phase I-II clinical studies to utilize iNKT cells using α-galactosylceramide-pulsed dendritic cells and identified leukotriene B4 12-hydroxydehydrogenase (LTB4DH) as a biomarker highly expressed in T cells derived from non-small cell lung cancer (NSCLC) patients who showed prolonged survival in respond to the iNKT cell immunotherapy. Because LTB4DH expression correlated with prolonged survival of NSCLC patients, we considered LTB4DH to play a role in iNKT cell immunotherapy. We herein demonstrate that the overexpression of LTB4DH in CD4⁺ or CD8⁺ T cells increases interferon-γ production and tumoricidal activity in the presence of prostaglandin E₂. Moreover, the expression of granzyme a, granzyme b, and perforin mRNA was increased in LTB4DH-overexpressing cells.

Keywords: CD4(+) T cell; CD8(+) T cell; Immunotherapy; LTB4DH; PGE(2); iNKT cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alcohol Oxidoreductases / genetics*
Alcohol Oxidoreductases / immunology
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / pathology
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / pathology
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / immunology
Carcinoma, Non-Small-Cell Lung / mortality
Carcinoma, Non-Small-Cell Lung / therapy*
Dendritic Cells / cytology
Dendritic Cells / drug effects
Dendritic Cells / immunology*
Dendritic Cells / transplantation
Dinoprostone / immunology
Dinoprostone / metabolism
Galactosylceramides / pharmacology*
Gene Expression Regulation, Neoplastic*
Granzymes / genetics
Granzymes / immunology
Humans
Immunotherapy / methods
Interferon-gamma / genetics
Interferon-gamma / immunology
K562 Cells
Lung Neoplasms / genetics
Lung Neoplasms / immunology
Lung Neoplasms / mortality
Lung Neoplasms / therapy*
Natural Killer T-Cells / drug effects
Natural Killer T-Cells / immunology
Natural Killer T-Cells / pathology
Perforin / genetics
Perforin / immunology
Primary Cell Culture
RNA, Messenger / genetics
RNA, Messenger / immunology
Signal Transduction
Survival Analysis

Substances

Galactosylceramides
IFNG protein, human
RNA, Messenger
alpha-galactosylceramide
Perforin
Interferon-gamma
Alcohol Oxidoreductases
leukotriene B4 12-hydroxydehydrogenase
GZMB protein, human
Granzymes
GZMA protein, human
Dinoprostone