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

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

doi:10.1016/j.ccell.2024.09.012

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

Cancer Cell. 2024 Oct 9:S1535-6108(24)00360-X. doi: 10.1016/j.ccell.2024.09.012. Online ahead of print.

Authors

Minjie Fu¹, Jiaxu Zhao², Licheng Zhang¹, Zhewei Sheng¹, Xiaohui Li², Fufang Qiu¹, Yuan Feng¹, Muyuan You¹, Hao Xu¹, Jinsen Zhang¹, Rui Zeng², Yang Huang², Cheng Li³, Wenhan Chen², Zheng Chen¹, Haibao Peng², Longzhi Li⁴, Yonghe Wu⁵, Dan Ye⁶, Yudan Chi⁷, Wei Hua⁸, Ying Mao⁹

Affiliations

¹ Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai 200040, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China.
² Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai 200032, China.
³ Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai 200032, China.
⁴ Department of General Surgery, Jing'an District Central Hospital of Shanghai, Huashan Hospital, Fudan University, Shanghai 200042, China.
⁵ Shanghai Institute for Advanced Immunochemical Studies (SIAIS), Shanghai Tech University, Shanghai 201210, China.
⁶ Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
⁷ Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
⁸ Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai 200040, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China. Electronic address: [email protected].
⁹ Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai 200040, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China; Research Unit of New Technologies of Micro-Endoscopy Combination in Skull Base Surgery (2018RU008), Chinese Academy of Medical Sciences, Beijing, China. Electronic address: [email protected].

PMID: 39423817
DOI: 10.1016/j.ccell.2024.09.012

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.