CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has been successful for the treatment of hematological cancers but less effective against solid tumors, a phenomenon that results from the immunosuppressive nature of the tumor microenvironment. As a strategy to improve the treatment of solid tumors, we applied CAR therapy to dendritic cells (DCs) to generate CAR-DCs. The CAR targeted the human epidermal growth factor receptor 2 (HER2) which is overexpressed in breast cancer to defeat the immunosuppressive nature of the tumor microenvironment. METHODS: CAR-DCs were generated by lentiviral vector transduction of SAMHD1 knock-out murine bone marrow-derived DCs. The vectors coexpressed CD40L and a soluble form of programmed cell death 1 (PD-1), a checkpoint inhibitor. To increase the durability of CAR-DCs, a gene encoding the cytokine GM-CSF was introduced into the CAR vector. The CAR-DCs were injected into mice bearing B16.HER2 melanoma tumors. Tumor growth was measured, and T cell functionality was determined by IFN expression and in vitro cytolytic assay. RESULTS: CAR-DCs suppressed the growth of B16.HER2 tumors and induced the proliferation and activation of tumor-infiltrating cytolytic CD8+T cells. The PD-1 checkpoint inhibitor further augmented the antitumor response and prevented T cell exhaustion. Vectored expression of GM-CSF increased the durability of the antitumor response. CONCLUSIONS: CAR-DCs could be an effective strategy for therapies against solid tumors that should be further explored. The approach relies on the antigen-presenting ability of DCs and their role in T cell activation and can be coupled with checkpoint inhibition in place of monoclonal antibody treatment.