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. [Display omitted] • TKI increases T cell infiltration in EGFR -mutant lung cancer brain metastases • TKI rewires the development fates of T cells by upregulating CTLA4 expression • Tumor-derived HMGB1 activates NF-κB signaling cascade in T cells • CTLA4 blockade synergizes with TKI and alleviates acquired resistance Fu et al. present a comprehensive analysis of the immune landscape within lung cancer brain metastases spanning different genetic backgrounds and TKI treatment scenarios. They report that CTLA4 blockade has synergetic efficacy with TKI in EGFR -mutant lung cancer brain metastases, offering a novel therapeutic avenue to combat TKI resistance. [ABSTRACT FROM AUTHOR]