LKB1 prevents ILC2 exhaustion to enhance antitumor immunity

Hongshen Niu; Huasheng Zhang; Dongdi Wang; Linfeng Zhao; Youqin Zhang; Wenyong Zhou; Jingjing Zhang; Xiaohui Su; Jiping Sun; Bing Su; Ju Qiu; Lei Shen

doi:10.1016/j.celrep.2023.113579

LKB1 prevents ILC2 exhaustion to enhance antitumor immunity

Cell Rep. 2024 Mar 27:113579. doi: 10.1016/j.celrep.2023.113579. Online ahead of print.

Authors

Hongshen Niu¹, Huasheng Zhang¹, Dongdi Wang¹, Linfeng Zhao¹, Youqin Zhang¹, Wenyong Zhou², Jingjing Zhang¹, Xiaohui Su¹, Jiping Sun¹, Bing Su¹, Ju Qiu³, Lei Shen⁴

Affiliations

¹ Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
³ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
⁴ Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: lshen@shsmu.edu.cn.

PMID: 38670109
DOI: 10.1016/j.celrep.2023.113579

Abstract

Group 2 innate lymphoid cells (ILC2s) play crucial roles in mediating allergic inflammation. Recent studies also indicate their involvement in regulating tumor immunity. The tumor suppressor liver kinase B1 (LKB1) inactivating mutations are associated with a variety of human cancers; however, the role of LKB1 in ILC2 function and ILC2-mediated tumor immunity remains unknown. Here, we show that ablation of LKB1 in ILC2s results in an exhausted-like phenotype, which promotes the development of lung melanoma metastasis. Mechanistically, LKB1 deficiency leads to a marked increase in the expression of programmed cell death protein-1 (PD-1) in ILC2s through the activation of the nuclear factor of activated T cell pathway. Blockade of PD-1 can restore the effector functions of LKB1-deficient ILC2s, leading to enhanced antitumor immune responses in vivo. Together, our results reveal that LKB1 acts to restrain the exhausted state of ILC2 to maintain immune homeostasis and antitumor immunity.

Keywords: CP: Cancer; CP: Immunology; anti-tumor immunity; exhaustion; group 2 innate lymphoid cells; liver kinase B1.