title: Fas-mediated T cell deletion potentiates tumor antigen-specific tolerance in a mouse model of prostate cancer.
abstract: A pivotal obstacle to cancer immunotherapy is peripheral T cell tolerance to tumor-associated antigens (TAAs). Tolerance induction among mature T cells in the periphery operates through a variety of mechanisms, including anergy and apoptosis. Although Fas-FasL-mediated apoptosis is a well-defined tolerance inducing mechanism, direct evidence of its interference with TAA-specific immunity in vivo is still lacking. In this report, we used the TRAMP mouse, which expresses SV40 large T antigen (Tag) preferentially in the prostate and develops prostate tumors, as a model system to address the role of Fas-mediated apoptosis in regulating peripheral T cell tolerance. Using RT-PCR and tetramer staining to quantify TAA-specific TCR-expressing cytolytic T lymphocytes (CTLs), we have shown the presence of TAA-specific CTLs at higher levels in TRAMP mice than in syngeneic C57Bl/6 mice. Tag-specific immunization led to the expansion of Tag-specific CTLs in C57Bl/6 mice, and to their elimination in TRAMP mice. Interestingly, in TRAMP mice with deficient Fas (Hybrid TRAMP-lpr/lpr), Tag-specific CTL elimination in response to Tag immunization did not take place. The results of cytolytic-function assays were consistent with induction and elimination patterns of TAA-specific CTLs and those of RT-PCR and tetramer staining. In conclusion, our data show that Fas-mediated TAA-specific CTL apoptosis contributes to T cell tolerance and suggest that such tolerance could be potentiated following TAA-specific immunization.
authors.affiliation: Departments of Urology and Pathology, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Tseng-Rogenski
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Arredouani
authors.forename: Yilin C
authors.initials: YC
authors.lastname: Neeley
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Martin G
authors.initials: MG
authors.lastname: Sanda
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D017209:Apoptosis; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D000952:Antigens, Polyomavirus Transforming; D019014:fas Receptor