CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy
Xue Bai, Ze-Qin Guo, Yan-Pei Zhang, Zhenzhen Fan, Lijuan Liu, Li Liu, Li-Li Long, Si-Cong Ma, Jian Wang, Yuan Fang, Xin-Ran Tang, Yu-Jie Zeng, Xinghua Pan, Dehua Wu, Zhong‐Yi Dong
Abstract
Abstract Liver kinase B1 ( LKB1 ) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras -driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1- deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8 + T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1 -deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity.