Journal Article

Target delivery of a PD-1-TREM2 scFv by CAR-T cells enhances anti-tumor efficacy in colorectal cancer

Huang, Xi, Li, Zhijian, Chen, Jian, Zeng, Qi, Zhu, Tianchuan, Jiang, Guanmin

2023

Overview

Background Chimeric antigen receptor (CAR) -T cell therapy is an efficient therapeutic strategy for specific hematologic malignancies. However, positive outcomes of this novel therapy in treating solid tumors are curtailed by the immunosuppressive tumor microenvironment (TME), wherein signaling of the checkpoint programmed death-1 (PD-1)/PD-L1 directly inhibits T-cell responses. Although checkpoint-targeted immunotherapy succeeds in increasing the number of T cells produced to control tumor growth, the desired effect is mitigated by the action of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the TME. Previous studies have confirmed that targeting triggering-receptor-expressed on myeloid cells 2 (TREM2) on TAMs and MDSCs enhances the outcomes of anti-PD-1 immunotherapy. Methods We constructed carcinoembryonic antigen (CEA)-specific CAR-T cells for colorectal cancer (CRC)-specific antigens with an autocrine PD-1-TREM2 single-chain variable fragment (scFv) to target the PD-1/PD-L1 pathway, MDSCs and TAMs. Results We found that the PD-1-TREM2-targeting scFv inhibited the activation of the PD-1/PD-L1 pathway. In addition, these secreted scFvs blocked the binding of ligands to TREM2 receptors present on MDSCs and TAMs, reduced the proportion of MDSCs and TAMs, and enhanced T-cell effector function, thereby mitigating immune resistance in the TME. PD-1-TREM2 scFv-secreting CAR-T cells resulted in highly effective elimination of tumors compared to that achieved with PD-1 scFv-secreting CAR-T therapy in a subcutaneous CRC mouse model. Moreover, the PD-1-TREM2 scFv secreted by CAR-T cells remained localized within tumors and exhibited an extended half-life. Conclusions Together, these results indicate that PD-1-TREM2 scFv-secreting CAR-T cells have strong potential as an effective therapy for CRC.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Alzheimer's disease / Antibodies / Antigens / Apoptosis / Autocrine signalling / Biomedical and Life Sciences / Biomedicine / Blood cancer / Cancer Research / Cancer therapies / CAR-T / Carcinoembryonic antigen / CEA (Oncology) / Cell therapy / Chimeric antigen receptors / Colorectal cancer / FDA approval / Genetic engineering / Health aspects / Immunotherapy / Laboratory animals / Lymphocytes / Lymphocytes T / Macrophages / Malignancy / Medical prognosis / Medical research / Molecular understanding and clinical aspects of immunotherapy in the treatment of cancer / Molecular weight / Myeloid cells / Oncology / PD-1 / PD-1 protein / PD-L1 protein / Penicillin / Proteins / Single-chain variable fragment (scFv) / Solid tumors / Stem cells / Suppressor cells / T cells / TREM2 / Tumor microenvironment / Tumors