肿瘤细胞治疗研究
英文原题：Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker.
Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker.
嵌合抗原受体（CAR）T 细胞治疗胶质母细胞瘤（GBM）面临的一大挑战是其免疫抑制性微环境，其中密集分布着促肿瘤的胶质瘤相关小胶质细胞和巨噬细胞（GAM）。
嵌合抗原受体（CAR）T细胞治疗胶质母细胞瘤（GBM）面临的一项重大挑战是其免疫抑制性微环境，其中促肿瘤性胶质瘤相关小胶质细胞和巨噬细胞（GAM）大量聚集。靶向CD47-信号调节蛋白α（SIRPα）轴的髓系免疫检查点疗法可诱导GAM吞噬功能，但单用CD47阻断存在毒性，且在实体瘤中生物利用度较低。本研究构建了靶向表皮生长因子受体变体III（EGFRvIII）的CAR T细胞，使其持续分泌一种对CD47具有高亲和力的信号调节蛋白γ相关蛋白（SGRP）。抗EGFRvIII-SGRP CAR T细胞可在体内清除原位EGFRvIII镶嵌型GBM，并促进GAM介导的肿瘤细胞吞噬。在皮下CD19阳性淋巴瘤小鼠模型中，抗CD19-SGRP CAR T细胞疗法优于常规抗CD19 CAR T细胞。因此，CAR与SGRP结合可清除旁观者肿瘤细胞，有望克服CAR T细胞疗法耐药的主要机制，包括免疫抑制和抗原逃逸。
A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive microenvironment, which is densely populated by protumoral glioma-associated microglia and macrophages (GAMs). Myeloid immune checkpoint therapy targeting the CD47-signal regulatory protein alpha (SIRP ) axis induces GAM phagocytic function, but CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. In this work, we engineer a CAR T cell against epidermal growth factor receptor variant III (EGFRvIII), constitutively secreting a signal regulatory protein gamma-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eradicate orthotopic EGFRvIII-mosaic GBM in vivo, promoting GAM-mediated tumor cell phagocytosis. In a subcutaneous CD19 + lymphoma mouse model, anti-CD19-SGRP CAR T cell therapy is superior to conventional anti-CD19 CAR T. Thus, combination of CAR and SGRP eliminates bystander tumor cells in a manner that could overcome main mechanisms of CAR T cell therapy resistance, including immune suppression and antigen escape.
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