Institute of Bioengineering and Nanotechnology, Singapore.
Department of Biological Sciences, National University of Singapore, Singapore.
PLoS One. 2019 May 9;14(5):e0216815. doi: 10.1371/journal.pone.0216815. eCollection 2019.
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.
利用诱导多能干细胞（iPSCs）衍生嵌合抗原受体修饰的 T 细胞（CAR-T 细胞）具有巨大的工业潜力。先前的一项研究使用αβ T 细胞衍生的 CAR 修饰的 iPSCs 来产生 CAR-T 细胞。然而，这些αβ T 细胞仅限于自体使用，并且只能识别单一的癌症抗原。为了使 CAR-T 细胞能够用于异体使用，我们将 γδ T 细胞重编程为 iPSCs（γδ T-iPSCs），以规避移植物抗宿主病的风险。为了靶向多个与癌症相关的抗原，我们使用了一种“NK 细胞促进”方案来分化 γδ T-iPSCs，并诱导自然杀伤受体（NKRs）的表达。通过这种两步策略，我们衍生出了具有一系列 NKRs 的模拟 γδ T 细胞，并将其命名为“γδ 自然杀伤 T（γδ NKT）细胞”。由于低/无抑制性杀伤细胞免疫球蛋白样受体（KIRs）和免疫检查点受体的表达，γδ NKT 细胞可能提供一种强大的“现成”细胞毒性细胞来源，以识别广谱癌症中多种普遍存在的抗原。
