Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition

Wendy Mao, Ali Ghasemzadeh, Zachary T. Freeman, Aleksandar Obradovic, Matthew G. Chaimowitz, Thomas R. Nirschl, Emily McKiernan, Srinivasan Yegnasubramanian, Charles G. Drake

Research output: Contribution to journalArticle

Abstract

Background: Prostate cancer responds poorly to current immunotherapies. Epigenetic therapies such as BET Bromodomain inhibition can change the transcriptome of tumor cells, possibly making them more immunogenic and thus susceptible to immune targeting. Methods: We characterized the effects of BET bromodomain inhibition using JQ1 on PD-L1 and HLA-ABC expression in two human prostate cell lines, DU145 and PC3. RNA-Seq was performed to assess changes on a genome-wide level. A cytotoxic T cell killing assay was performed in MC38-OVA cells treated with JQ1 to demonstrate increased immunogenicity. In vivo experiments in the Myc-Cap model were conducted to show the effects of JQ1 administration in concert with anti-CTLA-4 checkpoint blockade. Results: Here, we show that targeting BET bromodomains using the small molecule inhibitor JQ1 decreased PD-L1 expression and mitigated tumor progression in prostate cancer models. Mechanistically, BET bromodomain inhibition increased MHC I expression and increased the immunogenicity of tumor cells. Transcriptional profiling showed that BET bromodomain inhibition regulates distinct networks of antigen processing and immune checkpoint molecules. In murine models, treatment with JQ1 was additive with anti-CTLA-4 immunotherapy, resulting in an increased CD8/Treg ratio. Conclusions: BET Bromodomain inhibition can mediate changes in expression at a genome wide level in prostate cancer cells, resulting in an increased susceptibility to CD8 T cell targeting. These data suggest that combining BET bromodomain inhibition with immune checkpoint blockade may have clinical activity in prostate cancer patients.

Original languageEnglish (US)
Article number277
JournalJournal for immunotherapy of cancer
Volume7
Issue number1
DOIs
StatePublished - Oct 25 2019

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Prostatic Neoplasms
Immunotherapy
Genome
T-Lymphocytes
Neoplasms
Antigen Presentation
Transcriptome
Epigenomics
Prostate
RNA
Cell Line
Therapeutics

Keywords

  • BET
  • Bromodomain
  • Cancer immunology
  • CTLA-4
  • Epigenetic
  • Immune checkpoint blockade
  • Immune checkpoint inhibition
  • Immunotherapy
  • Prostate cancer
  • Treg

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Mao, W., Ghasemzadeh, A., Freeman, Z. T., Obradovic, A., Chaimowitz, M. G., Nirschl, T. R., ... Drake, C. G. (2019). Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition. Journal for immunotherapy of cancer, 7(1), [277]. https://doi.org/10.1186/s40425-019-0758-y

Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition. / Mao, Wendy; Ghasemzadeh, Ali; Freeman, Zachary T.; Obradovic, Aleksandar; Chaimowitz, Matthew G.; Nirschl, Thomas R.; McKiernan, Emily; Yegnasubramanian, Srinivasan; Drake, Charles G.

In: Journal for immunotherapy of cancer, Vol. 7, No. 1, 277, 25.10.2019.

Research output: Contribution to journalArticle

Mao, W, Ghasemzadeh, A, Freeman, ZT, Obradovic, A, Chaimowitz, MG, Nirschl, TR, McKiernan, E, Yegnasubramanian, S & Drake, CG 2019, 'Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition', Journal for immunotherapy of cancer, vol. 7, no. 1, 277. https://doi.org/10.1186/s40425-019-0758-y
Mao W, Ghasemzadeh A, Freeman ZT, Obradovic A, Chaimowitz MG, Nirschl TR et al. Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition. Journal for immunotherapy of cancer. 2019 Oct 25;7(1). 277. https://doi.org/10.1186/s40425-019-0758-y
Mao, Wendy ; Ghasemzadeh, Ali ; Freeman, Zachary T. ; Obradovic, Aleksandar ; Chaimowitz, Matthew G. ; Nirschl, Thomas R. ; McKiernan, Emily ; Yegnasubramanian, Srinivasan ; Drake, Charles G. / Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition. In: Journal for immunotherapy of cancer. 2019 ; Vol. 7, No. 1.
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abstract = "Background: Prostate cancer responds poorly to current immunotherapies. Epigenetic therapies such as BET Bromodomain inhibition can change the transcriptome of tumor cells, possibly making them more immunogenic and thus susceptible to immune targeting. Methods: We characterized the effects of BET bromodomain inhibition using JQ1 on PD-L1 and HLA-ABC expression in two human prostate cell lines, DU145 and PC3. RNA-Seq was performed to assess changes on a genome-wide level. A cytotoxic T cell killing assay was performed in MC38-OVA cells treated with JQ1 to demonstrate increased immunogenicity. In vivo experiments in the Myc-Cap model were conducted to show the effects of JQ1 administration in concert with anti-CTLA-4 checkpoint blockade. Results: Here, we show that targeting BET bromodomains using the small molecule inhibitor JQ1 decreased PD-L1 expression and mitigated tumor progression in prostate cancer models. Mechanistically, BET bromodomain inhibition increased MHC I expression and increased the immunogenicity of tumor cells. Transcriptional profiling showed that BET bromodomain inhibition regulates distinct networks of antigen processing and immune checkpoint molecules. In murine models, treatment with JQ1 was additive with anti-CTLA-4 immunotherapy, resulting in an increased CD8/Treg ratio. Conclusions: BET Bromodomain inhibition can mediate changes in expression at a genome wide level in prostate cancer cells, resulting in an increased susceptibility to CD8 T cell targeting. These data suggest that combining BET bromodomain inhibition with immune checkpoint blockade may have clinical activity in prostate cancer patients.",
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AU - Freeman, Zachary T.

AU - Obradovic, Aleksandar

AU - Chaimowitz, Matthew G.

AU - Nirschl, Thomas R.

AU - McKiernan, Emily

AU - Yegnasubramanian, Srinivasan

AU - Drake, Charles G.

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N2 - Background: Prostate cancer responds poorly to current immunotherapies. Epigenetic therapies such as BET Bromodomain inhibition can change the transcriptome of tumor cells, possibly making them more immunogenic and thus susceptible to immune targeting. Methods: We characterized the effects of BET bromodomain inhibition using JQ1 on PD-L1 and HLA-ABC expression in two human prostate cell lines, DU145 and PC3. RNA-Seq was performed to assess changes on a genome-wide level. A cytotoxic T cell killing assay was performed in MC38-OVA cells treated with JQ1 to demonstrate increased immunogenicity. In vivo experiments in the Myc-Cap model were conducted to show the effects of JQ1 administration in concert with anti-CTLA-4 checkpoint blockade. Results: Here, we show that targeting BET bromodomains using the small molecule inhibitor JQ1 decreased PD-L1 expression and mitigated tumor progression in prostate cancer models. Mechanistically, BET bromodomain inhibition increased MHC I expression and increased the immunogenicity of tumor cells. Transcriptional profiling showed that BET bromodomain inhibition regulates distinct networks of antigen processing and immune checkpoint molecules. In murine models, treatment with JQ1 was additive with anti-CTLA-4 immunotherapy, resulting in an increased CD8/Treg ratio. Conclusions: BET Bromodomain inhibition can mediate changes in expression at a genome wide level in prostate cancer cells, resulting in an increased susceptibility to CD8 T cell targeting. These data suggest that combining BET bromodomain inhibition with immune checkpoint blockade may have clinical activity in prostate cancer patients.

AB - Background: Prostate cancer responds poorly to current immunotherapies. Epigenetic therapies such as BET Bromodomain inhibition can change the transcriptome of tumor cells, possibly making them more immunogenic and thus susceptible to immune targeting. Methods: We characterized the effects of BET bromodomain inhibition using JQ1 on PD-L1 and HLA-ABC expression in two human prostate cell lines, DU145 and PC3. RNA-Seq was performed to assess changes on a genome-wide level. A cytotoxic T cell killing assay was performed in MC38-OVA cells treated with JQ1 to demonstrate increased immunogenicity. In vivo experiments in the Myc-Cap model were conducted to show the effects of JQ1 administration in concert with anti-CTLA-4 checkpoint blockade. Results: Here, we show that targeting BET bromodomains using the small molecule inhibitor JQ1 decreased PD-L1 expression and mitigated tumor progression in prostate cancer models. Mechanistically, BET bromodomain inhibition increased MHC I expression and increased the immunogenicity of tumor cells. Transcriptional profiling showed that BET bromodomain inhibition regulates distinct networks of antigen processing and immune checkpoint molecules. In murine models, treatment with JQ1 was additive with anti-CTLA-4 immunotherapy, resulting in an increased CD8/Treg ratio. Conclusions: BET Bromodomain inhibition can mediate changes in expression at a genome wide level in prostate cancer cells, resulting in an increased susceptibility to CD8 T cell targeting. These data suggest that combining BET bromodomain inhibition with immune checkpoint blockade may have clinical activity in prostate cancer patients.

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