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Updated: Jun 26, 2025

Utilizing a Comprehensive Immunoprecipitation Enrichment System to Identify an Endogenous Post-translational Modification Profile for Target Proteins
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Utilizing a Comprehensive Immunoprecipitation Enrichment System to Identify an Endogenous Post-translational Modification Profile for Target Proteins

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Posttranslational protein modifications as gatekeepers of cancer immunogenicity

Emanuela Marchese1,2, Shadmehr Demehri1,2

  • 1Center for Cancer Immunology, Krantz Family Center for Cancer Research, and.

The Journal of Clinical Investigation
|May 15, 2024
PubMed

Insights

Researchers explored targeting the OTUD4/CD73 pathway to combat triple-negative breast cancer (TNBC). Inhibiting OTUD4 (OTU domain-containing protein 4) restored T cell function and improved anti-PD-L1 therapy in preclinical models.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Triple-negative breast cancer (TNBC) is aggressive and characterized by an immunosuppressive tumor microenvironment (TME).
  • Elevated CD73 expression is a key marker of immunosuppression in TNBC.
  • The regulation of CD73 expression by OTUD4 (OTU domain-containing protein 4) in TNBC is not well understood.

Purpose of the Study:

  • To investigate the role of the OTUD4/CD73 axis in TNBC immunosuppression.
  • To evaluate the therapeutic potential of targeting this axis in preclinical TNBC models.

Main Methods:

  • Analysis of CD73 expression in TNBC.
  • Investigation of OTUD4-mediated posttranslational modifications regulating CD73.
  • Pharmacologic inhibition of OTUD4 using ST80 in preclinical TNBC models.
  • Assessment of cytotoxic T cell function and anti-PD-L1 therapy efficacy.

Main Results:

  • Elevated CD73 expression was identified as a hallmark of immunosuppression in TNBC.
  • OTUD4 was found to regulate CD73 expression through posttranslational modifications.
  • Pharmacologic inhibition of OTUD4 with ST80 restored cytotoxic T cell function.
  • Targeting the OTUD4/CD73 axis enhanced the efficacy of anti-PD-L1 therapy in preclinical TNBC models.

Conclusions:

  • The OTUD4/CD73 axis represents a promising therapeutic target for mitigating immunosuppression in TNBC.
  • Targeting OTUD4 may overcome resistance to immunotherapy in triple-negative breast cancer.

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