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.

中文翻译：

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用 CTLA4 阻断克服肺癌脑转移中的酪氨酸激酶抑制剂耐药


肺癌脑转移 （LCBM） 由于对酪氨酸激酶抑制剂 （TKI） 治疗的获得性耐药性，构成了重大的临床挑战。为了阐明其潜在机制，我们对手术获得的具有不同遗传背景和 TKI 治疗史的 LCBM 样本进行了单细胞 RNA 测序分析。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。这种免疫调节是由肿瘤来源的 HMGB1 响应 TKI 启动的。在具有 TKI 敏感或 TKI 耐药 EGFR 突变的 LCBM 同基因小鼠模型中，CTLA4 阻断与 TKI 联合治疗优于 TKI 单药治疗或联合 PD1 阻断的 TKI。这些发现提供了对 TKI 耐药机制的见解，并强调了 CTLA4 阻断在有效克服 LCBM 中 TKI 耐药的潜力。