近日，复旦大学毛颖等研究人员合作发现，通过CTLA4阻断能够克服肺癌脑转移中酪氨酸激酶抑制剂耐药性。这一研究成果于2024年10月17日在线发表在国际学术期刊《癌细胞》上。

研究人员表示，肺癌脑转移（LCBM）由于对酪氨酸激酶抑制剂（TKI）治疗产生的耐药性，成为临床上的重大挑战。

为了阐明其潜在机制，研究人员对具有不同遗传背景和TKI治疗史的外科获取的LCBM样本进行了单细胞RNA测序分析。

研究人员发现，TKI治疗增加了T细胞中免疫检查点CTLA4的表达，并促进了免疫抑制微环境的形成。

这种免疫调节由肿瘤来源的HMGB1在应对TKI时启动。在具有TKI敏感或TKI耐药EGFR突变的LCBM同基因小鼠模型中，将CTLA4阻断与TKI结合治疗的效果优于TKI单药治疗或TKI与PD1阻断的联合治疗。

这些发现揭示了TKI耐药机制，并强调了CTLA4阻断在有效克服LCBM中TKI耐药性方面的潜力。

附：英文原文

Title: Overcoming tyrosine kinase inhibitor resistance in lung cancer brain metastasis with CTLA4 blockade

Author: Minjie Fu, Jiaxu Zhao, Licheng Zhang, Zhewei Sheng, Xiaohui Li, Fufang Qiu, Yuan Feng, Muyuan You, Hao Xu, Jinsen Zhang, Rui Zeng, Yang Huang, Cheng Li, Wenhan Chen, Zheng Chen, Haibao Peng, Longzhi Li, Yonghe Wu, Dan Ye, Yudan Chi, Wei Hua, Ying Mao

Issue&Volume: 2024-10-17

Abstract: Lung cancer brain metastasis (LCBM) poses a significant clinical challenge due to acquired resistance to tyrosine kinase inhibitor (TKI) treatment. To elucidate its underlying mechanisms, we employed single-cell RNA sequencing analysis on surgically obtained LCBM samples with diverse genetic backgrounds and TKI treatment histories. Our study uncovers that TKI treatment elevates the immune checkpoint CTLA4 expression in T cells, promoting an immune-suppressive microenvironment. This immunomodulation is initiated by tumor-derived HMGB1 in response to TKIs. In LCBM syngeneic murine models with TKI-sensitive or TKI-resistant EGFR mutations, combining CTLA4 blockade with TKIs demonstrates enhanced efficacy over TKI monotherapy or TKIs with PD1 blockade. These findings provide insights into the TKI resistance mechanisms and highlight the potential of CTLA4 blockade in effectively overcoming TKI resistance in LCBM.

DOI: 10.1016/j.ccell.2024.09.012

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00360-X