利用 CTLA4 阻断剂克服肺癌脑转移中的酪氨酸激酶抑制剂耐药性

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2024-10-17 DOI:10.1016/j.ccell.2024.09.012

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, Ying Mao

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引用次数: 0

摘要

由于对酪氨酸激酶抑制剂（TKI）治疗的获得性耐药性，肺癌脑转移（LCBM）构成了重大的临床挑战。为了阐明其潜在机制，我们采用单细胞 RNA 测序分析法对不同遗传背景和 TKI 治疗史的 LCBM 手术样本进行了分析。我们的研究发现，TKI 治疗会提高 T 细胞中免疫检查点 CTLA4 的表达，促进免疫抑制微环境的形成。这种免疫调节是由肿瘤衍生的 HMGB1 对 TKIs 的反应引发的。在对 TKI 敏感或对 TKI 耐药的表皮生长因子受体突变 LCBM 合成小鼠模型中，CTLA4 阻断与 TKIs 的联合治疗比 TKI 单药或 TKIs 与 PD1 阻断联合治疗的疗效更佳。这些发现深入揭示了TKI耐药机制，并凸显了CTLA4阻断技术在有效克服LCBM中TKI耐药方面的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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

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

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.

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.