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

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...

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Detalles Bibliográficos
Autores principales: Yang, Zhaojuan, Xu, Guiqin, Wang, Boshi, Liu, Yun, Zhang, Li, Jing, Tiantian, Tang, Ming, Xu, Xiaoli, Jiao, Kun, Xiang, Lvzhu, Fu, Yujie, Tang, Daoqiang, Zhang, Xiaoren, Jin, Weilin, Zhuang, Guanglei, Zhao, Xiaojing, Liu, Yongzhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357983/
https://www.ncbi.nlm.nih.gov/pubmed/34381028
http://dx.doi.org/10.1038/s41467-021-25032-5
Descripción
Sumario: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.