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  3. Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer

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

  • Sci Immunol. 2023 Mar 17;8(81):eade4656. doi: 10.1126/sciimmunol.ade4656.
Yini Zhu 1 2,  Yun Zhao 1,  Jiling Wen 1,  Sheng Liu 3,  Tianhe Huang 1,  Ishita Hatial 4,  Xiaoxia Peng 1,  Hawraa Al Janabi 1,  Gang Huang 1,  Jackson Mittlesteadt 1,  Michael Cheng 5,  Atul Bhardwaj 4,  Brandon L Ashfeld 4,  Kenneth R Kao 6,  Dean Y Maeda 7,  Xing Dai 8,  Olaf Wiest 4,  Brian S J Blagg 4,  Xuemin Lu 1,  Liang Cheng 9 10,  Jun Wan 3 11 12,  Xin Lu 1 2 13
Affiliations

Affiliations

  • 1 Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
  • 2 Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA.
  • 3 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 4 Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN 46556, USA.
  • 5 Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 6 Terry Fox Cancer Research Labs, Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's Campus, NL A1B 3V6, Canada.
  • 7 Syntrix Biosystems Inc., Auburn, WA 98001, USA.
  • 8 Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, USA.
  • 9 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 10 Department of Pathology and Laboratory Medicine, Brown University Warren Alpert Medical School, Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, RI 02912, USA.
  • 11 Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 12 School of Informatics and Computing, Indiana University-Purdue University at Indianapolis, Indianapolis, IN 46202, USA.
  • 13 Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA.
PMID: 36897957 DOI: 10.1126/sciimmunol.ade4656
Abstract

The noninflamed microenvironment in prostate Cancer represents a barrier to immunotherapy. Genetic alterations underlying Cancer cell-intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 (PYGO2) as the driver oncogene for the amplicon at 1q21.3 in prostate Cancer. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the activation and infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/IDO1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the antitumor efficacy of immunotherapies using immune checkpoint blockade (ICB), adoptive cell transfer, or agents inhibiting myeloid-derived suppressor cells. In human prostate Cancer samples, Pygo2 expression was inversely correlated with the infiltration of CD8+ T cells. Analysis of the ICB clinical data showed association between high PYGO2 level and worse outcome. Together, our results highlight a potential path to improve immunotherapy using Pygo2-targeted therapy for advanced prostate Cancer.

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