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SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by
Marcella Fassò1, Rebecca Waitz, Yafei Hou
1Departments of Urology and Medicine, University of California, San Francisco, CA 94143, USA.
Abstract:
Discovery of immunologically relevant antigens in prostate cancer forms the basis for developing more potent active immunotherapy. We report here a strategy using the transgenic adenocarcinoma of mouse prostate (TRAMP) model, which allows for the functional identification of immunogenic prostate tumor antigens with relevance for human immunotherapy. Using a combination of active tumor vaccination in the presence of CTL-associated antigen 4 (CTLA-4) in vivo blockade, we elicited tumor-specific T cells used to expression clone the first T cell-defined TRAMP tumor antigen, called Spas-1 (stimulator of prostatic adenocarcinoma specific T cells-1). Spas-1 expression was increased in advanced primary TRAMP tumors. We show that the immunodominant SPAS-1 epitope SNC9-H(8) arose from a point mutation in one allele of the gene in TRAMP tumor cells, and that immunization with dendritic cells pulsed with SNC9-H(8) peptide resulted in protection against TRAMP-C2 tumor challenge. In humans, the Spas-1 ortholog SH3GLB2 has been reported to be overexpressed in prostate cancer metastases. Additionally, we identified a nonmutated HLA-A2-binding epitope in the human ortholog SH3GLB2, which primed T cells from healthy HLA-A2(+) individuals in vitro. Importantly, in vitro-primed T cells also recognized naturally processed and presented SH3GLB2. Our findings demonstrate that our in vivo CTLA-4 blockade-based T cell expression cloning can identify immunogenic cancer antigens with potential relevance for human immunotherapy.
Insights
Researchers identified Spas-1, a novel prostate cancer antigen, using a mouse model and CTLA-4 blockade. This discovery offers a new target for developing effective immunotherapies against prostate cancer.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Prostate cancer immunotherapy development relies on identifying immunologically relevant tumor antigens.
- The Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model is crucial for functional identification of antigens relevant to human immunotherapy.
Purpose of the Study:
- To identify novel, immunogenic prostate tumor antigens using a TRAMP model and CTLA-4 blockade.
- To evaluate the potential of identified antigens for human prostate cancer immunotherapy.
Main Methods:
- Utilized active tumor vaccination combined with in vivo CTLA-4 blockade in the TRAMP model.
- Employed T cell expression cloning to identify the Spas-1 antigen.
- Analyzed Spas-1 expression in TRAMP tumors and identified a specific immunodominant epitope (SNC9-H(8)).
- Assessed the human ortholog SH3GLB2 for expression in prostate cancer metastases and identified an HLA-A2-binding epitope.
Main Results:
- Successfully identified Spas-1 as the first T cell-defined TRAMP tumor antigen.
- Spas-1 expression was elevated in advanced TRAMP tumors.
- Immunization with the SNC9-H(8) peptide conferred protection against tumor challenge in the TRAMP model.
- The human ortholog SH3GLB2 is overexpressed in prostate cancer metastases, and a specific epitope primed T cells from healthy individuals.
Conclusions:
- The study successfully identified Spas-1, a T cell-defined antigen, and its immunodominant epitope in prostate cancer.
- The findings highlight the potential of Spas-1 and its human ortholog SH3GLB2 as targets for active immunotherapy in prostate cancer.
- The in vivo CTLA-4 blockade approach is effective for identifying immunogenic cancer antigens relevant to human immunotherapy.
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