USP12 downregulation orchestrates a protumourigenic microenvironment and enhances lung tumour resistance to PD-1 blockade

Zhaojuan Yang, Guiqin Xu, Boshi Wang, Yun Liu, Li Zhang, Tiantian Jing, Ming Tang, Xiaoli Xu, Kun Jiao, Lvzhu Xiang, Yujie Fu, Daoqiang Tang, Xiaoren Zhang, Weilin Jin, Guanglei Zhuang, Xiaojing Zhao () and Yongzhong Liu ()
Additional contact information
Zhaojuan Yang: Shanghai Jiao Tong University School of Medicine
Guiqin Xu: Shanghai Jiao Tong University School of Medicine
Boshi Wang: Shanghai Jiao Tong University School of Medicine
Yun Liu: Shanghai Jiao Tong University School of Medicine
Li Zhang: Shanghai Jiao Tong University School of Medicine
Tiantian Jing: Shanghai Jiao Tong University School of Medicine
Ming Tang: Shanghai Jiao Tong University School of Medicine
Xiaoli Xu: Shanghai Jiao Tong University School of Biomedical Engineering
Kun Jiao: Shanghai Jiao Tong University School of Biomedical Engineering
Lvzhu Xiang: Shanghai Jiao Tong University School of Medicine
Yujie Fu: Shanghai Jiao Tong University
Daoqiang Tang: Shanghai Jiao Tong University
Xiaoren Zhang: Guangzhou Medical University
Weilin Jin: The First Clinical Medical College of Lanzhou University
Guanglei Zhuang: Shanghai Jiao Tong University School of Medicine
Xiaojing Zhao: Shanghai Jiao Tong University
Yongzhong Liu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-25032-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25032-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-25032-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().