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Efficient Purification and LC-MS/MS-based Assay Development for Ten-Eleven Translocation-2 5-Methylcytosine Dioxygenase
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USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2

Lei-Lei Chen1, Matthew D Smith1, Lei Lv1

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Science Advances
|September 19, 2020
PubMed

Insights

USP15 deubiquitinase inhibits TET2 activity, impacting inflammatory pathways and anti-tumor immunity. Inhibiting USP15 enhances chemokine expression and T-cell infiltration, improving immunotherapy response in melanoma.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • TET2 dioxygenase is frequently mutated in hematopoietic malignancies and inactivated in solid tumors.
  • TET2 regulates the interferon-JAK-STAT pathway, influencing chemokine expression and tumor-infiltrating lymphocytes (TILs).
  • TET2 activity is promoted by monoubiquitylation at K1299.

Purpose of the Study:

  • To identify regulators of TET2 activity.
  • To investigate the role of USP15 in TET2 regulation.
  • To explore the therapeutic potential of targeting USP15 in solid tumors.

Main Methods:

  • Investigated USP15 as a TET2 deubiquitinase.
  • Analyzed TET2 and USP15 regulation of inflammatory gene expression.
  • Utilized gene deletion of Usp15 in melanoma mouse models.
  • Assessed chemokine expression, TILs, and immunotherapy response.

Main Results:

  • USP15 deubiquitylates TET2 at K1299, inhibiting its activity.
  • TET2 and USP15 exhibit opposing effects on inflammatory gene expression.
  • Usp15 deletion in melanoma enhances chemokine expression and TILs.
  • Usp15 deletion improves immunotherapy response and survival in tumor-bearing mice.

Conclusions:

  • USP15 is a novel negative regulator of TET2 activity.
  • USP15 deubiquitinase activity impacts anti-tumor immunity.
  • Targeting USP15 represents a potential therapeutic strategy for enhancing immunotherapy in solid tumors.

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