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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Development of a peptide-based vaccine targeting TMPRSS2:ERG fusion-positive prostate cancer
Haydn Thomas Kissick1, Martin George Sanda, Laura Kathleen Dunn
1Urology Division, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, E/CLS-447, Boston, MA, 02215, USA.
Abstract:
Identification of novel vaccine targets is critical for the design and advancement of prostate cancer (PCa) immunotherapy. Ideal targets are proteins that are abundant in prostate tumors while absent in extra-prostatic tissues. The fusion of the androgen-regulated TMPRSS2 gene with the ETS transcription factor ERG occurs in approximately 50 % of prostate cancer cases and results in aberrant ERG expression. Because expression of ERG is very low in peripheral tissue, we evaluated the suitability of this protein as an antigen target in PCa vaccines. ERG-derived HLA-A*0201-restricted immunogenic epitopes were identified through a 3-step strategy that included in silico, in vitro, and in vivo validation. Algorithms were used to predict potential HLA-A*0201-binding epitopes. High-scoring epitopes were tested for binding to HLA-A*0201 using the T2-based stabilization assay in vitro. Five peptides were found to bind HLA-A*0201 and were subsequently tested for immunogenicity in humanized, HLA-A*0201 transgenic mice. The in vivo screening identified three immunogenic peptides. One of these peptides, ERG295, overcame peripheral tolerance in HLA-A*0201 mice that expressed prostate-restricted ERG. Also, this peptide induced an antigen-specific response against ERG-expressing human prostate tumor cells. Finally, tetramer assay showed detectable and responsive ERG295-specific cytotoxic lymphocytes in peripheral blood of HLA-A*0201(+) prostate cancer patients. Detection of ERG-specific CTLs in both mice and the blood of prostate cancer patients indicates that ERG-specific tolerance can be overcome. Additionally, these data suggest that ERG is a suitable target antigen for PCa immunotherapy.
Insights
Researchers identified ERG as a promising prostate cancer (PCa) immunotherapy target. ERG-derived peptides, particularly ERG295, stimulated immune responses in mice and patients, suggesting potential for novel PCa vaccines.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Prostate cancer (PCa) immunotherapy requires identifying tumor-specific antigens.
- The TMPRSS2-ERG gene fusion in PCa leads to aberrant ERG expression, a potential target.
- ERG is expressed at low levels in healthy tissues, making it an ideal vaccine candidate.
Purpose of the Study:
- To evaluate the ERG protein as a target antigen for prostate cancer vaccines.
- To identify and validate ERG-derived epitopes for immunotherapy.
Main Methods:
- In silico prediction of HLA-A*0201-binding ERG epitopes.
- In vitro validation using T2-based stabilization assays for HLA-A*0201 binding.
- In vivo immunogenicity testing in HLA-A*0201 transgenic mice and analysis of patient samples.
Main Results:
- Five ERG-derived peptides bound to HLA-A*0201.
- Three peptides demonstrated immunogenicity in vivo, with ERG295 overcoming tolerance.
- ERG295 induced antigen-specific responses against ERG-expressing tumor cells.
- ERG295-specific cytotoxic lymphocytes (CTLs) were detected in prostate cancer patients.
Conclusions:
- ERG is a viable and suitable target antigen for prostate cancer immunotherapy.
- ERG-specific immune tolerance can be overcome, paving the way for ERG-based vaccines.
- The findings support the development of novel immunotherapies targeting ERG in prostate cancer.
