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

Marcella Fassò, Rebecca Waitz, Yafei Hou, Tae Rim, Norman M. Greenberg, Nilabh Shastri, Lawrence Fong, James P. Allison

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)3509-3514
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number9
DOIs
StatePublished - Mar 4 2008
Externally publishedYes

Keywords

  • Immunotherapy
  • Prostatic neoplasms
  • T cell antigen
  • TRAMP mice

ASJC Scopus subject areas

  • General

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