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, Yongzhong Liu, Yongzhong Liu, Yongzhong Liu
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 Kras G12D -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.