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Updated: Apr 20, 2026
In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
A chimeric antigen receptor for TRAIL-receptor 1 induces apoptosis in various types of tumor cells
Eiji Kobayashi1, Hiroyuki Kishi1, Tatsuhiko Ozawa1
1Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Abstract:
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its associated receptors (TRAIL-R/TR) are attractive targets for cancer therapy because TRAIL induces apoptosis in tumor cells through TR while having little cytotoxicity on normal cells. Therefore, many agonistic monoclonal antibodies (mAbs) specific for TR have been produced, and these induce apoptosis in multiple tumor cell types. However, some TR-expressing tumor cells are resistant to TR-specific mAb-induced apoptosis. In this study, we constructed a chimeric antigen receptor (CAR) of a TRAIL-receptor 1 (TR1)-specific single chain variable fragment (scFv) antibody (TR1-scFv-CAR) and expressed it on a Jurkat T cell line, the KHYG-1 NK cell line, and human peripheral blood lymphocytes (PBLs). We found that the TR1-scFv-CAR-expressing Jurkat cells killed target cells via TR1-mediated apoptosis, whereas TR1-scFv-CAR-expressing KHYG-1 cells and PBLs killed target cells not only via TR1-mediated apoptosis but also via CAR signal-induced cytolysis, resulting in cytotoxicity on a broader range if target cells than with TR1-scFv-CAR-expressing Jurkat cells. The results suggest that TR1-scFv-CAR could be a new candidate for cancer gene therapy.
Insights
Chimeric antigen receptors targeting TRAIL-receptor 1 (TR1) show promise for cancer therapy. TR1-scFv-CAR engineered immune cells induce tumor cell apoptosis and cytolysis, offering a new gene therapy approach.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Therapy
Background:
- Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) targets cancer cells via TRAIL receptors (TR).
- Resistance to TRAIL-receptor specific monoclonal antibodies (mAbs) limits current cancer therapy efficacy.
- Chimeric antigen receptors (CARs) offer a novel approach to enhance targeted cancer cell apoptosis.
Purpose of the Study:
- To engineer and evaluate a chimeric antigen receptor (CAR) based on a TRAIL-receptor 1 (TR1)-specific single chain variable fragment (scFv) antibody (TR1-scFv-CAR).
- To assess the efficacy of TR1-scFv-CAR expression in different immune cell types for cancer gene therapy.
Main Methods:
- Construction of a TR1-scFv-CAR.
- Expression of TR1-scFv-CAR on Jurkat T cells, KHYG-1 NK cells, and human peripheral blood lymphocytes (PBLs).
- Evaluation of target cell killing via TR1-mediated apoptosis and CAR signal-induced cytolysis.
Main Results:
- TR1-scFv-CAR-expressing Jurkat cells induced target cell apoptosis via TR1.
- TR1-scFv-CAR-expressing KHYG-1 cells and PBLs exhibited enhanced cytotoxicity through both TR1-mediated apoptosis and CAR signal-induced cytolysis.
- CAR-engineered immune cells demonstrated broader target cell killing compared to Jurkat cells alone.
Conclusions:
- TR1-scFv-CAR engineered immune cells effectively target and kill cancer cells.
- The combination of TR1-mediated apoptosis and CAR signal-induced cytolysis broadens the therapeutic potential.
- TR1-scFv-CAR represents a promising candidate for novel cancer gene therapy strategies.
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