肿瘤细胞治疗研究
英文原题：Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen.
我们证明了利用 TCR-T 治疗胶质母细胞瘤的原理验证。
T细胞受体工程化T细胞（TCR-T）通过能够安全且广泛地靶向胶质母细胞瘤来源的肽组，可能在胶质母细胞瘤中具有优势。蛋白酪氨酸磷酸酶受体Z1型（PTPRZ1）是一种临床上可靶向的胶质母细胞瘤抗原，与胶质母细胞瘤细胞干性相关。在这里，我们从一名接种过疫苗的胶质母细胞瘤患者中鉴定出一种治疗性HLA-A*02限制性PTPRZ1反应性TCR。原发性脑肿瘤的单细胞测序显示，PTPRZ1在恶性细胞中过表达，尤其是在胶质母细胞瘤干细胞（GSCs）和星形胶质细胞样细胞中。经验证的疫苗诱导TCR可识别内源性加工的抗原，且无脱靶交叉反应性。PTPRZ1特异性TCR-T（PTPRZ1-TCR-T）以抗原特异性方式杀伤靶细胞，并且在小鼠实验性脑肿瘤中，其静脉内和脑室内联合给药有效。PTPRZ1-TCR-T在体外和体内维持干细胞记忆表型，并裂解所有检测的HLA-A*02 + 原发性胶质母细胞瘤细胞系，且对GSCs和星形胶质细胞样细胞具有偏好性。总之，我们证明了利用TCR-T治疗胶质母细胞瘤的原理验证。
T cell receptor-engineered T cells (TCR-T) could be advantageous in glioblastoma by allowing safe and ubiquitous targeting of the glioblastoma-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), is a clinically targetable glioblastoma antigen associated with glioblastoma cell stemness. Here, we identify a therapeutic HLA-A*02-restricted PTPRZ1-reactive TCR retrieved from a vaccinated glioblastoma patient. Single-cell sequencing of primary brain tumors shows PTPRZ1 overexpression in malignant cells, especially in glioblastoma stem cells (GSCs) and astrocyte-like cells. The validated vaccine-induced TCR recognizes the endogenously processed antigen without off-target cross-reactivity. PTPRZ1-specific TCR-T (PTPRZ1-TCR-T) kill target cells antigen-specifically, and in murine experimental brain tumors, their combined intravenous and intracerebroventricular administration is efficacious. PTPRZ1-TCR-T maintain stem cell memory phenotype in vitro and in vivo and lyse all examined HLA-A*02 + primary glioblastoma cell lines with a preference for GSCs and astrocyte-like cells. In summary, we demonstrate the proof of principle to employ TCR-T to treat glioblastoma.
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