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.

Highlights

  • chimeric antigen receptor (CAR)-T cells have been proven to be promising modalities of adoptive cellular therapy (Hillerdal et al, 2014; June et al, 2018)

  • A comparably higher level of PD-1 expression was found in TR141928BBζ CAR-T cells than in TR1419-28ζ or TR1419-BBζ CAR-T cells after co-incubation with SW480, which was in line with the findings shown before that PD-1 was more frequently expressed by the TR1419-28BBζ CAR-transduced T cells (Figures 1F,G)

  • We demonstrated that the third-generation TR1419-28BBζ CAR-T cells showed functional advances in vitro

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Summary

Introduction

CAR-T cells have been proven to be promising modalities of adoptive cellular therapy (Hillerdal et al, 2014; June et al, 2018). CARs are composed of an antigen recognition domain of a single-chain variable fragment (scFv), hinge region, transmembrane domain, intracellular signaling region, co-stimulatory domain, and CD3ζ chain (Hillerdal and Essand, 2015; Du et al, 2019; Ramello et al, 2019). The scFv region is responsible for the binding of the antigenic target, and the co-stimulation domain plays an essential role in promoting the expansion and antitumor effects of CAR-T cells, while greatly related to the design of the scFv structure (Guedan et al, 2018). It has been reported that the phenotypic and functional optimizations of CAR-T cells largely rely on the design of the scFv and the corresponding second- or third-generation co-stimulatory domains (Savoldo et al, 2011; Golumba-Nagy et al, 2018; Sun et al, 2020)

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