TRAIL-R1-Targeted CAR-T Cells Exhibit Dual Antitumor Efficacy

Yaru Nai; Li Du; Meiying Shen; Tingting Li; Jingjing Huang; Xiaojian Han; Feiyang Luo; Wang Wang; Da Pang; Aishun Jin

doi:10.3389/fmolb.2021.756599

TRAIL-R1-Targeted CAR-T Cells Exhibit Dual Antitumor Efficacy

Front Mol Biosci. 2021 Dec 20:8:756599. doi: 10.3389/fmolb.2021.756599. eCollection 2021.

Authors

Yaru Nai^{1

2}, Li Du^{1

2}, Meiying Shen^{3

4}, Tingting Li^{1

2}, Jingjing Huang^{1

2}, Xiaojian Han^{1

2}, Feiyang Luo^{1

2}, Wang Wang^{1

2}, Da Pang³, Aishun Jin^{1

2}

Affiliations

¹ Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing, China.
² Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, China.
³ Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
⁴ Department of Endocrine Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) has limited expression in normal tissues but was highly expressed in various types of tumors, making it an attractive target for cancer immunotherapy. Here, we utilized the single-chain variable fragment (scFv) from our previously identified TRAIL-R1-targeting monoclonal antibody (TR1⁴¹⁹) with antitumor efficacy and produced the TR1⁴¹⁹ chimeric antigen receptor (CAR) T cells. We characterized the phenotypes and functions of these CAR-T cells and found that the third-generation TR1⁴¹⁹-28BBζ CAR-T cells exhibited greater target sensitivity and proliferative capability, with slightly higher PD-1 expression after antigen stimulation. Importantly, we found that the TR1⁴¹⁹ CAR-T cells could induce TRAIL-R1-positive tumor cell death via a dual mechanism of the death receptor-dependent apoptosis as well as the T-cell-mediated cytotoxicity. Altogether, the TR1⁴¹⁹ CAR-T cells could serve as a promising strategy for targeting the TRAIL-R1-positive tumors.

Keywords: CAR-T; TRAIL-R1; apoptosis; cytotoxicity; third generation.