Immunotherapy for Prostate Cancer: An Evolving Landscape

Mao, Wendy; Drake, Charles G.

doi:10.1007/978-3-319-62431-0_35

Cited by 2 publications

(3 citation statements)

References 69 publications

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“…Prostate cancer is the second leading cause of cancer-related death in U.S. men [1]. Despite advances in immunotherapy, immune checkpoint blockade has yet to confer significant benefit for patients with prostate cancer [2–4]. This resistance to immunotherapy may be due in part to the fact that prostate cancer is poorly infiltrated by cytotoxic T-cells as compared to other solid tumors [4].…”

Section: Introductionmentioning

confidence: 99%

“…Despite advances in immunotherapy, immune checkpoint blockade has yet to confer significant benefit for patients with prostate cancer [2–4]. This resistance to immunotherapy may be due in part to the fact that prostate cancer is poorly infiltrated by cytotoxic T-cells as compared to other solid tumors [4]. Since PD-1 / PD-L1 blockade functions by blocking the inhibitory interactions between tumor cells and T-cells, much of its mechanism of action relies on the presence of a pre-existing anti-tumor T cell response [5].…”

Section: Introductionmentioning

confidence: 99%

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Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition

Mao¹,

Ghasemzadeh²,

Freeman³

et al. 2019

j. immunotherapy cancer

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BackgroundProstate 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.MethodsWe 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.ResultsHere, 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.ConclusionsBET 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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition

Mao¹,

Ghasemzadeh²,

Freeman³

et al. 2019

j. immunotherapy cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…These data are consistent with clinical data showing that the use of immunotherapy has generally met with limited clinical success in prostate cancer. 3 …”

Section: Discussionmentioning

confidence: 99%