Abstract
Using induced pluripotent stem cells (iPSCs) to derive chimeric antigen receptor-modified T (CAR-T) cells has great industrial potential. A previous study used αβ T cell-derived CAR-modified iPSCs to produce CAR-T cells. However, these αβ T cells are restricted to autologous use and only recognize single cancer antigen. To make CAR-T alternative for allogeneic use, we reprogrammed γδ T cell into iPSCs (γδ T-iPSCs) to circumvent the risk of graft-versus-host disease. To target multiple cancer-associated antigens, we used an “NK cell-promoting” protocol to differentiate γδ T-iPSCs and to induce expression of natural killer receptors (NKRs). Through such two-step strategy, mimetic γδ T cells endowed with an array of NKRs and thus designated as “γδ natural killer T (γδ NKT) cells” were derived. With no/low-level expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) and immune checkpoint receptors, γδ NKT cells may provide a potent “off-the-shelf” cytotoxic cell source to recognize multiple ubiquitous antigens in a broad spectrum of cancers.
Highlights
Clinical success of CD19-targeting chimeric antigen receptor-modified T (CAR-T) cells in treating B-cell malignancies symbolizes the translation of synthetic immunology into cellular immunotherapy[1, 2]
Designing a synthetic strategy to derive mimetic Vγ9Vδ2 T cells endowed with natural killer receptors (NKRs) from induced pluripotent stem cells (iPSCs)
It has been demonstrated that an antigen-specific αβ T cell can be reprogrammed into iPSCs, which will still carry the same rearranged TCRA and TCRB genes and that such αβ T cell-derived iPSCs can be re-differentiated into αβ T cells, which will re-express the same antigen-specific αβ T cell receptors (αβ TCRs)[23, 24]
Summary
Clinical success of CD19-targeting chimeric antigen receptor-modified T (CAR-T) cells in treating B-cell malignancies symbolizes the translation of synthetic immunology into cellular immunotherapy[1, 2]. To generate unlimited CAR-T cells, Themeli et al previously described a three-step strategy that combined induced pluripotent stem cell (iPSC) and CAR technologies[3]: Firstly, αβ T cells were reprogrammed to generate αβ T cell-derived iPSCs (αβ TiPSCs); αβ T-iPSCs were genetically modified with CAR gene to generate CAR-modified αβ T-iPSCs (CAR-αβ T-iPSCs); lastly, CAR-αβ T-iPSCs were differentiated to generate CAR-T cells. Such iPSC derivatives express αβ T cell receptors (αβ TCRs) and may cause graft-versus-host disease (GvHD) in allogeneic therapies [4].
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