Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer
<b>Background/Objectives</b>: Androgen receptor (AR) expression and signaling are critical for the progression of prostate cancer and have been the therapeutic focus of prostate cancer for over 50 years. While a variety of agents have been developed to target this axis, many of these fai...
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MDPI AG
2024-11-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/12/11/1273 |
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| author | Robert D. Marek Selena Halabi Mu-En Wang Jason McBane Junping Wei Tao Wang Xiao Yang Congxiao Liu Gangjun Lei Herbert Kim Lyerly Ming Chen Timothy N. Trotter Zachary C. Hartman |
| author_facet | Robert D. Marek Selena Halabi Mu-En Wang Jason McBane Junping Wei Tao Wang Xiao Yang Congxiao Liu Gangjun Lei Herbert Kim Lyerly Ming Chen Timothy N. Trotter Zachary C. Hartman |
| author_sort | Robert D. Marek |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: Androgen receptor (AR) expression and signaling are critical for the progression of prostate cancer and have been the therapeutic focus of prostate cancer for over 50 years. While a variety of agents have been developed to target this axis, many of these fail due to the emergent expression of AR RNA splice variants, such as AR-V7, that can signal independently of ligand binding. Other therapies, such as vaccination against prostate-specific antigens, have achieved FDA approvals but have fallen short of being incorporated as standard-of-care therapies for advanced prostate cancer. This may be due to the elevated level of immunosuppression observed in prostate cancer, which remains largely refractory to immune checkpoint blockade. <b>Methods</b>: We developed a vaccine targeting AR-V7, a common isoform associated with treatment resistance, and demonstrated its ability to elicit AR-V7-specific immunity and enable anti-tumor responses against AR-V7+ cancers in subcutaneous tumor models. <b>Results</b>: Our studies also revealed that AR-V7 expression conferred an immune suppressive phenotype that was significant in a non-AR-dependent prostate cancer model. Notably, in this model, we found that vaccination in combination with enzalutamide, an AR antagonist, suppressed these aggressive immune suppressive cancers and resulted in enhanced survival in comparison to control vaccinated and enzalutamide-treated mice. While anti-PD-1 immune checkpoint inhibition (ICI) alone slowed tumor growth, the majority of vaccinated mice that received anti-PD-1 therapy showed complete tumor elimination. <b>Conclusions</b>: Collectively, these results validate the importance of AR signaling in prostate cancer immune suppression and suggest the potential of AR-V7-specific vaccines as therapeutic strategies against prostate cancer, offering significant protective and therapeutic anti-tumor responses, even in the presence of androgen signaling inhibitors. |
| format | Article |
| id | doaj-art-c963995c0b8d4b7f83e39d65de5281db |
| institution | OA Journals |
| issn | 2076-393X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj-art-c963995c0b8d4b7f83e39d65de5281db2025-08-20T02:04:41ZengMDPI AGVaccines2076-393X2024-11-011211127310.3390/vaccines12111273Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate CancerRobert D. Marek0Selena Halabi1Mu-En Wang2Jason McBane3Junping Wei4Tao Wang5Xiao Yang6Congxiao Liu7Gangjun Lei8Herbert Kim Lyerly9Ming Chen10Timothy N. Trotter11Zachary C. Hartman12Department of Pathology, Duke University, Durham, NC 27710, USADepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USADepartment of Pathology, Duke University, Durham, NC 27710, USADepartment of Surgery, Duke University, Durham, NC 27777, USADepartment of Surgery, Duke University, Durham, NC 27777, USADepartment of Surgery, Duke University, Durham, NC 27777, USADepartment of Surgery, Duke University, Durham, NC 27777, USADepartment of Surgery, Duke University, Durham, NC 27777, USADepartment of Surgery, Duke University, Durham, NC 27777, USADuke Cancer Institute, Duke University, Durham, NC 2771, USADepartment of Pathology, Duke University, Durham, NC 27710, USADepartment of Surgery, Duke University, Durham, NC 27777, USADepartment of Pathology, Duke University, Durham, NC 27710, USA<b>Background/Objectives</b>: Androgen receptor (AR) expression and signaling are critical for the progression of prostate cancer and have been the therapeutic focus of prostate cancer for over 50 years. While a variety of agents have been developed to target this axis, many of these fail due to the emergent expression of AR RNA splice variants, such as AR-V7, that can signal independently of ligand binding. Other therapies, such as vaccination against prostate-specific antigens, have achieved FDA approvals but have fallen short of being incorporated as standard-of-care therapies for advanced prostate cancer. This may be due to the elevated level of immunosuppression observed in prostate cancer, which remains largely refractory to immune checkpoint blockade. <b>Methods</b>: We developed a vaccine targeting AR-V7, a common isoform associated with treatment resistance, and demonstrated its ability to elicit AR-V7-specific immunity and enable anti-tumor responses against AR-V7+ cancers in subcutaneous tumor models. <b>Results</b>: Our studies also revealed that AR-V7 expression conferred an immune suppressive phenotype that was significant in a non-AR-dependent prostate cancer model. Notably, in this model, we found that vaccination in combination with enzalutamide, an AR antagonist, suppressed these aggressive immune suppressive cancers and resulted in enhanced survival in comparison to control vaccinated and enzalutamide-treated mice. While anti-PD-1 immune checkpoint inhibition (ICI) alone slowed tumor growth, the majority of vaccinated mice that received anti-PD-1 therapy showed complete tumor elimination. <b>Conclusions</b>: Collectively, these results validate the importance of AR signaling in prostate cancer immune suppression and suggest the potential of AR-V7-specific vaccines as therapeutic strategies against prostate cancer, offering significant protective and therapeutic anti-tumor responses, even in the presence of androgen signaling inhibitors.https://www.mdpi.com/2076-393X/12/11/1273prostate cancerandrogen receptorvaccinescastration resistanceimmune suppressionimmune checkpoint inhibition |
| spellingShingle | Robert D. Marek Selena Halabi Mu-En Wang Jason McBane Junping Wei Tao Wang Xiao Yang Congxiao Liu Gangjun Lei Herbert Kim Lyerly Ming Chen Timothy N. Trotter Zachary C. Hartman Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer Vaccines prostate cancer androgen receptor vaccines castration resistance immune suppression immune checkpoint inhibition |
| title | Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer |
| title_full | Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer |
| title_fullStr | Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer |
| title_full_unstemmed | Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer |
| title_short | Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer |
| title_sort | vaccination against androgen receptor splice variants to immunologically target prostate cancer |
| topic | prostate cancer androgen receptor vaccines castration resistance immune suppression immune checkpoint inhibition |
| url | https://www.mdpi.com/2076-393X/12/11/1273 |
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