Generation of Antitumor T Cells from Embryonic Stem Cells Modified with Tumor Antigen-Specific TCR Genes

摘要

Antitumor T cell receptor (TCR)-modified T cell (TCR-T) therapy is a specific immunotherapy with great potential for application. However, T cell preparation for TCR-T therapy is an individualized process that is poorly managed by industry standards. The lack of suitable animal models for preclinical experiments also delays the development of TCR-T therapy. To solve these problems, we combined TCR and embryonic stem (ES) cell technologies to produce antigen-specific mouse T cells using TCR-modified mouse ES (mES) cells specific for a human HLA-A2-restricted MAGE-A1 peptide. To establish a human HLA-TCR antigen recognition system in mouse T cells, we used MAGE-A1-specific TCR and HLA-A2 as models to generate human and mouse hybrid (T1367 and HHD) MHC and TCR molecules and then modified the mES and OP9-DL1 cell lines with the T1367 and HHD genes, respectively. T1367 gene-modified mES cells (T1367-mES) maintained pluripotency and differentiated into the major tissue types of all three dermal layers in vivo. Eight weeks after subcutaneous co-injection of T1367-mES and OP9-DL1-HHD (OP9-DH) cells into NOD/SCID mice, we generated ES cell-derived teratomas. Mature T cells were detected in the peripheral blood and spleen and were specific for MAGE-A1. In the future, we hope to improve this method with 3D nanotechnologies for the increasing the bone marrow formation in teratoma and translate it to human TCR-iPS cells. Human T cells differentiated from TCR-iPS cells could be applied in adoptive immunotherapy for cancer.