Severe heterogeneity within glioblastoma has spurred the notion that disrupting the interplay between multiple elements on immunosuppression is at the core of meaningful anti-tumor responses. T cell immunoreceptor with Ig and ITIM domains (TIGIT) and its glioblastoma-associated antigen, CD155, form a highly immunosuppressive axis in glioblastoma and other solid tumors, yet targeting of TIGIT, a functionally heterogeneous receptor on tumor-infiltrating immune cells, has largely been ineffective as monotherapy, suggesting that disruption of its inhibitory network might be necessary for measurable responses. It is within this context that we show that the usurpation of the TIGIT − CD155 axis via engineered synNotch-mediated activation of induced pluripotent stem cell-derived natural killer (NK) cells promotes transcription factor-mediated activation of a downstream signaling cascade that results in the controlled, localized blockade of CD73 to disrupt purinergic activity otherwise resulting in the production and accumulation of immunosuppressive extracellular adenosine. Such “decoy” receptor engages CD155 binding to TIGIT, but tilts inhibitory TIGIT/CD155 interactions toward activation via downstream synNotch signaling. Usurping activities of TIGIT and CD73 promotes the function of adoptively transferred NK cells into intracranial patient-derived models of glioblastoma and enhances their natural cytolytic functions against this tumor to result in complete tumor eradication. In addition, targeting both receptors, in turn, reprograms the glioblastoma microenvironment via the recruitment of T cells and the downregulation of M2 macrophages. This study demonstrates that TIGIT/CD155 and CD73 are targetable receptor partners in glioblastoma. Our data show that synNotch-engineered pluripotent stem cell-derived NK cells are not only effective mediators of anti-glioblastoma responses within the setting of CD73 and TIGIT/CD155 co-targeting, but represent a powerful allogeneic treatment option for this tumor.

胶质母细胞瘤内的严重异质性激发了这样一种观念，即破坏免疫抑制中多种因素之间的相互作用是有意义的抗肿瘤反应的核心。具有 Ig 和 ITIM 结构域的 T 细胞免疫受体 (TIGIT) 及其胶质母细胞瘤相关抗原 CD155 在胶质母细胞瘤和其他实体瘤中形成高度免疫抑制轴，但针对肿瘤浸润免疫细胞的功能异质受体 TIGIT 的靶向作用在很大程度上已被证实。作为单一疗法无效，这表明其抑制网络的破坏可能是可测量的反应所必需的。正是在这种背景下，我们表明，通过工程化的 synNotch 介导的诱导多能干细胞衍生的自然杀伤 (NK) 细胞的激活，篡夺 TIGIT – CD155 轴，促进转录因子介导的下游信号级联的激活，从而导致对 CD73 进行受控的局部阻断，以破坏嘌呤能活性，否则会导致免疫抑制性细胞外腺苷的产生和积累。这种“诱饵”受体使 CD155 与 TIGIT 结合，但通过下游 synNotch 信号传导使抑制性 TIGIT/CD155 相互作用倾向于激活。篡夺 TIGIT 和 CD73 的活性可促进过继转移的 NK 细胞进入颅内患者来源的胶质母细胞瘤模型的功能，并增强其针对该肿瘤的天然细胞溶解功能，从而完全根除肿瘤。此外，针对这两种受体，反过来会通过 T 细胞的募集和 M2 巨噬细胞的下调来重新编程胶质母细胞瘤微环境。这项研究表明 TIGIT/CD155 和 CD73 是胶质母细胞瘤中的靶向受体伴侣。 我们的数据表明，synNotch 工程化的多能干细胞衍生的 NK 细胞不仅是 CD73 和 TIGIT/CD155 共靶向环境中抗胶质母细胞瘤反应的有效介质，而且代表了该肿瘤的强大同种异体治疗选择。