FBXO38 mediates FGL1 ubiquitination and degradation to enhance cancer immunity and suppress inflammation

Tongguan Tian; Xiao Xie; Wanwan Yi; Yuefan Zhou; Yixin Xu; Zhenxiang Wang; Junjing Zhang; Mingen Lin; Ruonan Zhang; Zhongwei Lv; Xinxing Li; Lei Lv; Yanping Xu

doi:10.1016/j.celrep.2023.113362

FBXO38 mediates FGL1 ubiquitination and degradation to enhance cancer immunity and suppress inflammation

Cell Rep. 2023 Nov 28;42(11):113362. doi: 10.1016/j.celrep.2023.113362. Epub 2023 Nov 7.

Authors

Tongguan Tian¹, Xiao Xie², Wanwan Yi³, Yuefan Zhou¹, Yixin Xu¹, Zhenxiang Wang¹, Junjing Zhang¹, Mingen Lin⁴, Ruonan Zhang⁴, Zhongwei Lv³, Xinxing Li¹, Lei Lv⁵, Yanping Xu⁶

Affiliations

¹ Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China.
² Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
³ Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.
⁴ MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
⁵ MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: lvlei@fudan.edu.cn.
⁶ Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China. Electronic address: yanpingxu@tongji.edu.cn.

PMID: 37938970
DOI: 10.1016/j.celrep.2023.113362

Abstract

Upregulation of FGL1 helps tumors escape from immune surveillance, and therapeutic antibodies targeting FGL1 have potential as another immune checkpoint inhibitor. However, the underlying mechanism of high FGL1 protein level in cancers is not well defined. Here, we report that FBXO38 interacts with and ubiquitylates FGL1 to negatively regulate its stability and to mediate cancer immune response. Depletion of FBXO38 markedly augments FGL1 abundance, not only suppressing CD8⁺ T cell infiltration and enhancing immune evasion of tumor but also increasing inflammation in mice. Importantly, we observe a negative correlation of FBXO38 with FGL1 and IL-6 in non-small cell lung cancer specimens. FGL1 and IL-6 levels positively correlate with TNM (tumor, lymph node, metastasis) stages, while FBXO38 and the infiltrating CD8⁺ T cells negatively correlate with TNM stages. Our study identifies a mechanism regulating FGL1 stability and a target to enhance the immunotherapy and suggests that the combination of anti-FGL1 and anti-IL-6 is a potential therapeutic strategy for cancer immunotherapy.

Keywords: CP: Cancer; CP: Immunology; FBXO38; FGL1; immunotherapy; non-small cell lung cancer; ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Carcinoma, Non-Small-Cell Lung*
Inflammation
Interleukin-6
Lung Neoplasms*
Mice
Ubiquitination

Substances

Interleukin-6
Fgl1 protein, mouse
Fbxo38 protein, mouse