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Virus Delivery of CRISPR Guides to the Murine Prostate for Gene Alteration
Published on: April 27, 2018
Reversing enhancer RNA-mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models
Xiang Li1,2,3, Rui Sun1,3, Hao Li1,3
1Department of Urology, Institute of Urologic Science and Technology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Immunotherapy has been effective in many cancer types but has failed in multiple clinical trials in prostate cancers, with the underlying mechanisms remaining largely unclear. Here, we demonstrate that androgen receptor pathway inhibitor (ARPI) plus irradiation (IR) triggered robust anticancer immunity in prostate cancers in both patients and mice. We show that androgen-activated AR suppressed innate immune signaling by inducing inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) gene repression through HDAC2 interaction with an IKBKE enhancer RNA (IKBKE eRNA, or IKBKE-e). ARPI treatment caused IKBKE derepression and enhanced an IR-induced innate immune response via action of RIG-I and MDA5 dsRNA sensors. IKBKE-e ablation largely enhanced innate immunity in prostate cancer cells in culture and anticancer immunity in mice. Our results revealed AR, HDAC2, and IKBKE eRNA as critical intrinsic immune suppressors in prostate cancer cells, suggesting that rejuvenating inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) signaling by targeting IKBKE-e is an actionable strategy to elicit synthetic anticancer immunity in immunologically "cold" cancers such as prostate cancer.
Insights
Androgen receptor pathway inhibitors plus irradiation boost prostate cancer immunity by reactivating IKBKE signaling. This strategy targets immune suppressors, enhancing innate immunity against "cold" tumors.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Prostate cancer immunotherapy has shown limited success, with mechanisms poorly understood.
- Androgen receptor (AR) signaling is crucial in prostate cancer progression and immune evasion.
Purpose of the Study:
- To investigate the mechanisms by which androgen receptor pathway inhibitors (ARPI) and irradiation (IR) enhance anticancer immunity in prostate cancer.
- To identify key molecular players involved in immune suppression within prostate cancer cells.
Main Methods:
- Analysis of patient and mouse prostate cancer models treated with ARPI and IR.
- Investigated the role of AR, HDAC2, and IKBKE enhancer RNA (eRNA) in regulating innate immune signaling.
- Utilized gene ablation of IKBKE-e to assess its impact on immune responses.
Main Results:
- ARPI plus IR treatment induced robust anticancer immunity in prostate cancer.
- Androgen-activated AR suppresses innate immunity via HDAC2-mediated repression of IKBKE eRNA.
- ARPI treatment derepressed IKBKE, enhancing IR-induced innate immunity through RIG-I and MDA5 sensors.
- Ablation of IKBKE-e significantly boosted innate and anticancer immunity.
Conclusions:
- AR, HDAC2, and IKBKE eRNA are critical intrinsic immune suppressors in prostate cancer.
- Rejuvenating IKKε signaling by targeting IKBKE-e is a promising strategy for inducing synthetic anticancer immunity in "cold" cancers like prostate cancer.
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