Chih Yu-Chan, Dietsch Amelie C, Koopmann Philipp, Ma Xiujian, Agardy Dennis A, Zhao Binghao, De Roia Alice, Kourtesakis Alexandros, Kilian Michael, Krämer Christopher, Suwala Abigail K, Stenzinger Miriam, Boenig Halvard, Blum Agnieszka, Pienkowski Victor Murcia, Aman Kuralay, Becker Jonas P, Feldmann Henrike, Bunse Theresa, Harbottle Richard, Riemer Angelika B, Liu Hai-Kun, Etminan Nima, Sahm Felix, Ratliff Miriam, Wick Wolfgang, Platten Michael, Green Edward W, Bunse Lukas
Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany.
Nat Commun. 2025 Feb 1;16(1):1262. doi: 10.1038/s41467-025-56547-w.
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-A02-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-A02 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.
通过对源自胶质母细胞瘤的肽组进行安全且广泛的靶向，工程化T细胞受体的T细胞（TCR-T）在胶质母细胞瘤治疗中可能具有优势。蛋白酪氨酸磷酸酶Z1型受体（PTPRZ1）是一种与胶质母细胞瘤细胞干性相关的具有临床靶向性的胶质母细胞瘤抗原。在此，我们鉴定出一种从接种疫苗的胶质母细胞瘤患者中获取的治疗性HLA-A02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，疫苗诱导的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）可抗原特异性地杀伤靶细胞，在小鼠实验性脑肿瘤中，静脉内和脑室内联合给药有效。PTPRZ1-TCR-T在体外和体内均维持干细胞记忆表型，并优先裂解所有检测的HLA-A02原发性胶质母细胞瘤细胞系，尤其是GSCs和星形胶质细胞样细胞。总之，我们证明了使用TCR-T治疗胶质母细胞瘤的原理验证。
