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

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 (TR1(419)) with antitumor efficacy and produced the TR1(419) chimeric antigen receptor (CAR) T cells. We characterized the phenotypes and functions of these CAR-T cells and found that the third-generation TR1(419)-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 TR1(419) 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 TR1(419) CAR-T cells could serve as a promising strategy for targeting the TRAIL-R1–positive tumors.