SPAS-1 (stimulator of prostatic adenocarcinomaspecific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade Journal Article
| Authors: | Fassò, M.; Waitz, R.; Hou, Y.; Rim, T.; Greenberg, N. M.; Shastri, N.; Fong, L.; Allison, J. P. |
| Article Title: | SPAS-1 (stimulator of prostatic adenocarcinomaspecific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade |
| 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. © 2008 by The National Academy of Sciences of the USA. |
| Keywords: | controlled study; protein expression; carrier protein; unclassified drug; genetics; nonhuman; molecular genetics; methodology; t lymphocyte; t-lymphocytes; mouse; animal; animals; mice; allele; mus; dendritic cell; animal experiment; animal model; in vivo study; tumor antigen; transgenic mouse; mice, transgenic; prostatic neoplasms; molecular cloning; cloning, molecular; t lymphocyte receptor; immunology; chemistry; molecular sequence data; immunotherapy; antigens, neoplasm; cancer vaccine; cancer vaccines; nucleotide sequence; prostate tumor; carrier proteins; cancer immunization; immunodominant epitopes; t-cell antigen receptor specificity; epitope; adaptor proteins, signal transducing; base sequence; antigens, cd; point mutation; cytotoxic t lymphocyte antigen 4; isolation and purification; signal transducing adaptor protein; leukocyte antigen; t lymphocyte activation; antigens, differentiation; differentiation antigen; cytotoxic t-lymphocyte antigen 4; t lymphocyte antigen; t cell antigen; tramp mice; spas1 antigen; sh3glb2 protein, human; sh3glb2 protein, mouse |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 105 |
| Issue: | 9 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2008-03-04 |
| Start Page: | 3509 |
| End Page: | 3514 |
| Language: | English |
| DOI: | 10.1073/pnas.0712269105 |
| PUBMED: | 18303116 |
| PROVIDER: | scopus |
| PMCID: | PMC2265147 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 12" - "Export Date: 17 November 2011" - "CODEN: PNASA" - "Molecular Sequence Numbers: GENBANK: AF257319, EF676083, EF676083;" - "Source: Scopus" |
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