Prof. Xu Chenqi from the School of Life Science, HIAS, UCAS, was invited to publish an article entitled "Screening for the next-generation T cell therapies" in the academic journal Cancer Cell, introducing and looking into the recent research on T cell therapies published in Cancer Cell.
Adoptive transfer of genetically modified immune cells (like CAR-T and TCR-T cells) holds great promise for cancer immunotherapy, but its clinical application is limited to hematoma. CRISPR knockin targeting can improve cell therapies, but more high-throughput methods are needed to test which knockin gene constructs most potently enhance primary cell functionsin vivo. Recently, Alexander Marson's research group at the University of California, San Francisco, developed pooled knockin technology for genetic modification of T-cell immunotherapy. The study was published in Cell on April 16, 2020. Researchers developed a widely adaptable technology to barcode and track targeted integrations of large non-viral DNA templates by inserting a specific T-cell receptor (TCR) and genes of interest into the coding region of endogenous TCR genes through homologous recombination, and applied the technology to perform pooled knockin screens in primary human T cells. They carried out pooled knockin of 36 different templates into the coding region of TCR genes. To measure the functions of T cells more comprehensively, they further developed pooled knockin sequencing (PoKI-seq), combining single-cell transcriptome analysis and pooled knockin screening to measure cell abundance and cell stateex vivo andin vivo. With the technology, researchers nominated a novel TGF-βR2-41BB chimeric receptor that improved solid tumor clearance of T cells. Pooled knockin screening enables knockin of multiple endogenous genetic sequences to accelerate discovery of cell therapies.
The study accelerates the discovery of novel T-cell therapies by combining T-cell therapies with CRISPR, while combination with single-cell sequencing enables a comprehensive measure of the functions and potential of T cells in terms of cell abundance and cell status. In this study, genetic screening is still focused on signaling molecules, while T cells in the tumor microenvironment face dual pressure of glucose and oxidation metabolism, and their metabolic programming is significantly different from normal conditions. Therefore, metabolism-related genetic screening may point the way for next-generation T cell therapies.
