Derivation Of Mimetic Gamma Delta T Cells Endowed With Cancer Recognition Receptors From Reprogrammed Gamma Delta T Cell

Using induced pluripotent stem cells (iPSCs) to derive chimeric antigen receptor-modified T (CAR-T) cells has great industrial potential. A previous study used alpha beta T cell-derived CAR-modified iPSCs to produce CAR-T cells. However, these alpha beta T cells are restricted to autologous use and only recognize single cancer antigen. To make CAR-T alternative for allogeneic use, we reprogrammed gamma delta T cell into iPSCs (gamma delta 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 gamma delta T-iPSCs and to induce expression of natural killer receptors (NKRs). Through such two-step strategy, mimetic gamma delta T cells endowed with an array of NKRs and thus designated as "gamma delta natural killer T (gamma delta NKT) cells" were derived. With no/low-level expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) and immune checkpoint receptors, gamma delta NKT cells may provide a potent "off-the-shelf" cytotoxic cell source to recognize multiple ubiquitous antigens in a broad spectrum of cancers.