Reversing enhancer RNA–mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models
Xiang Li, Rui Sun, Hao Li, Jacob J. Orme, Xu Zhang, Yu Hou, Sean S. Park, Yu Zhang, Yi He, Liguo Wang, Veronica Rodriguez-Bravo, Josep Domingo-Domenech, Shancheng Ren, Dan Xia, Guanghou Fu, Zhankui Jia, Haojie Huang
Xiang Li, Rui Sun, Hao Li, Jacob J. Orme, Xu Zhang, Yu Hou, Sean S. Park, Yu Zhang, Yi He, Liguo Wang, Veronica Rodriguez-Bravo, Josep Domingo-Domenech, Shancheng Ren, Dan Xia, Guanghou Fu, Zhankui Jia, Haojie Huang
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Research Article Immunology Oncology

Reversing enhancer RNA–mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models

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.

Authors

Xiang Li, Rui Sun, Hao Li, Jacob J. Orme, Xu Zhang, Yu Hou, Sean S. Park, Yu Zhang, Yi He, Liguo Wang, Veronica Rodriguez-Bravo, Josep Domingo-Domenech, Shancheng Ren, Dan Xia, Guanghou Fu, Zhankui Jia, Haojie Huang

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Figure 7

IR and antiandrogen dual treatment sensitizes prostate cancer cells to ICI therapy.

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IR and antiandrogen dual treatment sensitizes prostate cancer cells to I...
(A) Illustration of the mouse treatment. Myc-CaP cells were injected s.c. into the right flank of mice. After 7 days, tumors were treated with or without IR (6 Gy), ENZ (10 mg/kg), and/or InVivoMAb anti–mouse PD-1 antibody (10 mg/kg). (B–D) Tumors from mice in each group at day 21 were harvested and photographed (B). Tumor growth was measured every other day for 21 days. Tumor volumes at each time point were measured (C), and dot plots show tumor weights for mice in each group at day 21 (D). (E–H) CD4+ and CD8+ T cells in PBMCs (E and F) and tumors (G and H) were analyzed by FACS. (I) Illustration of the mouse treatment. C4-2 cells were injected s.c. into the right flank of BRGSF-HIS mice. After 7 days, tumors were treated with or without IR and IKBKE-eRNA ASO (10 mg/kg). (J–L) Tumor growth was measured every other day for 21 days. Tumor growth over the 21-day period (K). Tumors in each group at day 21 were harvested and photographed (J), and tumor weights were measured (L). (M and N) CD45+CD4+ (M) and CD45+CD8+ (N) lymphocytes in PBMCs of mice treated as indicated were analyzed by FACS. (O and P) Tumor tissues from mice treated as indicated were digested, and infiltrated CD45+CD4+ (O) and CD45+CD8+ (P) lymphocytes were analyzed by FACS. Data are displayed as the mean ± SD (n = 5) (C–H and K–P). Significance was determined by 2-way ANOVA (C–H and K–P).