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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, and Ying Mao
Overcoming tyrosine kinase inhibitor resistance in lung cancer brain metastasis with CTLA4 blockade
- Field of Research：cancer
- Research Methods：HE|mIHC|Flow cytometry|IHC|Western blot
- Species：human
- Sample Type：lung cancer
- Models：Lung cancer brain metastasis (LCBM)
- Journal：Cancer Cell
- Time：November 11, 2024
- Product line：mIHC
- Key words：
TKI、HMGB1、CTLA4、NF-kB signaling、T cell infiltration
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.
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