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

Autor: Xiaoli Xu, Yongzhong Liu, Lvzhu Xiang, Yujie Fu, Tiantian Jing, Li Zhang, Xiaojing Zhao, Daoqiang Tang, Zhaojuan Yang, Kun Jiao, Boshi Wang, Guiqin Xu, Xiaoren Zhang, Yun Liu, Ming Tang, Weilin Jin, Guanglei Zhuang
Rok vydání: 2021
Předmět:
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-021-25032-5
Popis: 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.
The cancer cell-extrinsic roles of deubiquitinases are unclear. Here the authors show that deubiquitinase USP12 downregulation contributes to development of an immune-suppressive tumour microenvironment in KRAS-driven lung cancers and mechanistically this is through the insufficient deubiquitination of the NF-κB inhibitor, PPM1B.
Databáze: OpenAIRE
Externí odkaz: