SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade.
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.
Fassò
Marcella
M
Departments of Urology and Medicine, University of California, San Francisco, CA 94143, USA.
Waitz
Rebecca
R
Hou
Yafei
Y
Rim
Tae
T
Greenberg
Norman M
NM
Shastri
Nilabh
N
Fong
Lawrence
L
Allison
James P
JP
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000302:isolation & purification*; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm / Q000276:immunology / Q000302:isolation & purification*; D001483:Base Sequence; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D003001:Cloning, Molecular / Q000379:methods*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017354:Point Mutation; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D002352:Carrier Proteins; C556707:Ctla4 protein, mouse; D016056:Immunodominant Epitopes; C486098:SH3GLB2 protein, human; C528122:Sh3glb2 protein, mouse