Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Department of Neurosurgery, Georgetown University Medical Center, Washington, DC, USA.
Cytotherapy. 2022 Aug;24(8):802-817. doi: 10.1016/j.jcyt.2022.04.001. Epub 2022 May 17.
T cell-based therapies like genetically modified immune cells expressing chimeric antigen receptors have shown robust anti-cancer activity in vivo, especially in patients with blood cancers. However, extending this approach to an "off-the-shelf" setting can be challenging, as allogeneic T cells carry a significant risk of graft-versus-host disease (GVHD). By contrast, allogeneic natural killer (NK) cells recognize malignant cells without the need for prior antigen exposure and have been used safely in multiple cancer settings without the risk of GVHD. However, similar to T cells, NK cell function is negatively impacted by tumor-induced transforming growth factor beta (TGF-β) secretion, which is a ubiquitous and potent immunosuppressive mechanism employed by most malignancies. Allogeneic NK cells for adoptive immunotherapy can be sourced from peripheral blood (PB) or cord blood (CB), and the authors' group and others have previously shown that ex vivo expansion and gene engineering can overcome CB-derived NK cells' functional immaturity and poor cytolytic activity, including in the presence of exogenous TGF-β. However, a direct comparison of the effects of TGF-β-mediated immune suppression on ex vivo-expanded CB- versus PB-derived NK cell therapy products has not previously been performed. Here the authors show that PB- and CB-derived NK cells have distinctive gene signatures that can be overcome by ex vivo expansion. Additionally, exposure to exogenous TGF-β results in an upregulation of inhibitory receptors on NK cells, a novel immunosuppressive mechanism not previously described. Finally, the authors provide functional and genetic evidence that both PB- and CB-derived NK cells are equivalently susceptible to TGF-β-mediated immune suppression. The authors believe these results provide important mechanistic insights to consider when using ex vivo-expanded, TGF-β-resistant PB- or CB-derived NK cells as novel immunotherapy agents for cancer.
基于 T 细胞的疗法，如表达嵌合抗原受体的基因修饰免疫细胞，在体内显示出强大的抗癌活性，尤其在血液癌患者中。然而，将这种方法扩展到“现成的”环境可能具有挑战性，因为异基因 T 细胞携带重大的移植物抗宿主病（GVHD）风险。相比之下，异基因自然杀伤（NK）细胞在无需预先暴露抗原的情况下识别恶性细胞，并且已在多种癌症环境中安全使用，而没有 GVHD 的风险。然而，与 T 细胞类似，NK 细胞的功能受到肿瘤诱导的转化生长因子β（TGF-β）分泌的负面影响，这是大多数恶性肿瘤采用的普遍且有效的免疫抑制机制。用于过继免疫疗法的异基因 NK 细胞可以来源于外周血（PB）或脐带血（CB），作者小组和其他小组先前表明，体外扩增和基因工程可以克服 CB 来源的 NK 细胞的功能不成熟和低细胞溶解活性，包括在存在外源性 TGF-β的情况下。然而，以前尚未对 TGF-β 介导的免疫抑制对体外扩增的 CB-与 PB-来源的 NK 细胞治疗产品的影响进行直接比较。在这里，作者表明 PB-和 CB-来源的 NK 细胞具有独特的基因特征，可以通过体外扩增克服。此外，暴露于外源性 TGF-β会导致 NK 细胞上抑制性受体的上调，这是以前未描述的新型免疫抑制机制。最后，作者提供了功能和遗传证据，表明 PB-和 CB-来源的 NK 细胞都同样容易受到 TGF-β 介导的免疫抑制。作者认为这些结果为使用体外扩增、TGF-β 抗性的 PB-或 CB-来源的 NK 细胞作为癌症的新型免疫治疗剂提供了重要的机制见解。
