美国西北大学Peiwen Chen团队发现，Kunitz型蛋白酶抑制剂TFPI2可重塑胶质母细胞瘤的干性和免疫抑制性肿瘤微环境。2023年9月4日，《自然—免疫学》杂志在线发表了这项成果。

据研究人员介绍，胶质母细胞瘤（GBM）肿瘤由多种细胞群组成，包括自我更新的胶质母细胞瘤干细胞（GSC）和免疫抑制性小胶质细胞。

研究人员发现Kunitz型蛋白酶抑制剂TFPI2是连接这些细胞群及其相关的GBM干性和免疫抑制特征的关键因素。TFPI2通过激活c-Jun N-末端激酶-信号转导和转录激活因子（STAT）3通路促进GSC自我更新和肿瘤生长。分泌的TFPI2与小胶质细胞上的功能受体CD51相互作用，通过激活STAT6信号引发小胶质细胞的浸润和免疫抑制性极化。抑制TFPI2-CD51-STAT6信号轴可激活T细胞，并与GBM小鼠模型中的抗PD1治疗产生协同作用。在人类GBM中，TFPI2与干性、小胶质细胞丰度、免疫抑制和不良预后呈正相关。

这项研究确定了TFPI2的功能，并支持将TFPI2作为治疗GBM的有效策略。

附：英文原文

Title: Kunitz-type protease inhibitor TFPI2 remodels stemness and immunosuppressive tumor microenvironment in glioblastoma

Author: Pang, Lizhi, Dunterman, Madeline, Guo, Songlin, Khan, Fatima, Liu, Yang, Taefi, Erfan, Bahrami, Atousa, Geula, Changiz, Hsu, Wen-Hao, Horbinski, Craig, James, Charles David, Chen, Peiwen

Issue&Volume: 2023-09-04

Abstract: Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase–signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2–CD51–STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. In human GBM, TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis. Our study identifies a function for TFPI2 and supports therapeutic targeting of TFPI2 as an effective strategy for GBM.

DOI: 10.1038/s41590-023-01605-y

Source: https://www.nature.com/articles/s41590-023-01605-y