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

Zhaojuan Yang1, Guiqin Xu1, Boshi Wang1

  • 1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Nature Communications
|August 12, 2021
PubMed

Insights

Downregulation of USP12 in Kras-driven lung cancer promotes tumor growth and immune suppression. Inhibiting USP12 reduces sensitivity to anti-PD-1 immunotherapy, highlighting its role in cancer progression and treatment response.

Area of Science:

  • Oncology
  • Cancer Biology
  • Immunology

Background:

  • KRAS activation drives tumor growth and immune evasion.
  • AKT-mTOR signaling is implicated in various cancers.
  • USP12 is a deubiquitinase with potential roles in cancer.

Purpose of the Study:

  • Investigate the role of USP12 in Kras-driven lung cancer.
  • Elucidate the mechanisms by which USP12 affects the tumor microenvironment.
  • Determine the impact of USP12 on anti-PD-1 immunotherapy response.

Main Methods:

  • Analysis of USP12 expression in KrasG12D mouse lung tumors and human NSCLC.
  • Assessment of tumor growth, immune cell infiltration, and vascularization.
  • Investigation of downstream signaling pathways including PPM1B and NF-κB.
  • Evaluation of USP12 inhibition effects on anti-PD-1 therapy in mouse models.

Main Results:

  • USP12 is downregulated in Kras-driven lung tumors due to AKT-mTOR activation.
  • USP12 loss promotes tumor growth, immunosuppression, macrophage recruitment, and reduced T cell activity.
  • USP12 downregulation leads to a pro-tumorigenic secretome via PPM1B/NF-κB pathway.
  • USP12 inhibition impairs anti-PD-1 immunotherapy efficacy.

Conclusions:

  • USP12 is a critical downstream mediator of oncogenic KRAS signaling in lung cancer.
  • USP12 loss promotes tumor progression and immune evasion.
  • USP12 targeting impacts tumor-immune interactions and immunotherapy response, suggesting therapeutic potential.

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