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Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in

Yini Zhu1,2, Yun Zhao1, Jiling Wen1

  • 1Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.

Science Immunology
|March 10, 2023
PubMed

Insights

Targeting Pygopus 2 (PYGO2) in prostate cancer can overcome immunotherapy resistance. Inhibiting PYGO2 enhances T cell activity, reduces tumor growth, and improves responses to cancer treatments.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Prostate cancer's noninflamed microenvironment hinders immunotherapy effectiveness.
  • Genetic alterations in cancer cells significantly influence the tumor immune landscape.
  • Pygopus 2 (PYGO2) is identified as a key oncogene at the 1q21.3 amplicon in prostate cancer.

Purpose of the Study:

  • To investigate the role of Pygopus 2 (PYGO2) in prostate cancer progression and immune evasion.
  • To explore the therapeutic potential of targeting PYGO2 to enhance immunotherapy efficacy.

Main Methods:

  • Utilized transgenic mouse models of metastatic prostate adenocarcinoma.
  • Assessed the impact of Pygo2 deletion on tumor progression, metastasis, and survival.
  • Analyzed immune cell infiltration, activation, and tumor cell sensitivity to T cell killing.
  • Investigated the underlying signaling pathways regulated by Pygo2.
  • Evaluated the efficacy of Pygo2 inhibition in combination with various immunotherapies.
  • Correlated Pygo2 expression with immune cell infiltration and clinical outcomes in human prostate cancer samples.

Main Results:

  • Pygo2 deletion decelerated tumor progression, reduced metastases, and extended survival in mouse models.
  • Loss of Pygo2 increased cytotoxic T lymphocyte (CTL) activation and infiltration, sensitizing tumors to T cell-mediated killing.
  • Pygo2 was found to regulate a p53/Sp1/Kit/Ido1 signaling network that creates an immunosuppressive microenvironment.
  • Inhibition of Pygo2, genetically or pharmacologically, enhanced the antitumor effects of immune checkpoint blockade, adoptive cell transfer, and myeloid-derived suppressor cell inhibitors.
  • Human prostate cancer samples showed an inverse correlation between Pygo2 expression and CD8+ T cell infiltration.
  • High PYGO2 levels in patients correlated with poorer outcomes in immune checkpoint blockade therapy.

Conclusions:

  • Pygopus 2 (PYGO2) plays a critical role in promoting prostate cancer growth and immune evasion.
  • Targeting PYGO2 represents a promising strategy to overcome immunotherapy resistance in advanced prostate cancer.
  • Combined Pygo2-targeted therapy with existing immunotherapies could significantly improve patient outcomes.

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