CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy

Xue Bai, Ze-Qin Guo, Yan-Pei Zhang, Zhen-zhen Fan, Li-Juan Liu, Li Liu, Li-Li Long, Si-Cong Ma, Jian Wang, Yuan Fang, Xin-Ran Tang, Yu-Jie Zeng, Xinghua Pan (), Wu De-Hua () and Zhong-Yi Dong ()
Additional contact information
Xue Bai: Southern Medical University
Ze-Qin Guo: Southern Medical University
Yan-Pei Zhang: Southern Medical University
Zhen-zhen Fan: China National Center for Bioinformation
Li-Juan Liu: Southern Medical University, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application
Li Liu: Southern Medical University
Li-Li Long: Southern Medical University
Si-Cong Ma: Southern Medical University
Jian Wang: Southern Medical University
Yuan Fang: Southern Medical University
Xin-Ran Tang: Southern Medical University
Yu-Jie Zeng: Southern Medical University
Xinghua Pan: Southern Medical University, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application
Wu De-Hua: Southern Medical University
Zhong-Yi Dong: Southern Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-18

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.

Date: 2023
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DOI: 10.1038/s41467-023-36892-4

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