SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade

Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3509-14. doi: 10.1073/pnas.0712269105. Epub 2008 Feb 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / isolation & purification*
  • Animals
  • Antigens, CD
  • Antigens, Differentiation
  • Antigens, Neoplasm / immunology
  • Antigens, Neoplasm / isolation & purification*
  • Base Sequence
  • CTLA-4 Antigen
  • Cancer Vaccines / immunology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Cloning, Molecular / methods*
  • Humans
  • Immunodominant Epitopes / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Point Mutation
  • Prostatic Neoplasms / chemistry*
  • Prostatic Neoplasms / immunology
  • T-Cell Antigen Receptor Specificity
  • T-Lymphocytes / immunology


  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Antigens, Differentiation
  • Antigens, Neoplasm
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cancer Vaccines
  • Carrier Proteins
  • Ctla4 protein, mouse
  • Immunodominant Epitopes
  • SH3GLB2 protein, human
  • Sh3glb2 protein, mouse

Associated data

  • GENBANK/EF676083