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

Author:

Zhu Yini12ORCID,Zhao Yun1ORCID,Wen Jiling1ORCID,Liu Sheng3,Huang Tianhe1ORCID,Hatial Ishita4,Peng Xiaoxia1,Al Janabi Hawraa1,Huang Gang1,Mittlesteadt Jackson1ORCID,Cheng Michael5ORCID,Bhardwaj Atul4ORCID,Ashfeld Brandon L.4ORCID,Kao Kenneth R.6,Maeda Dean Y.7ORCID,Dai Xing8ORCID,Wiest Olaf4ORCID,Blagg Brian S.J.4,Lu Xuemin1,Cheng Liang910ORCID,Wan Jun31112ORCID,Lu Xin1213ORCID

Affiliation:

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.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine,Immunology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3