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Fas-mediated T cell deletion potentiates tumor antigen-specific tolerance in a mouse model of prostate cancer

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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.

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Abbreviations

CTL:

Cytotoxic T lymphocyte

TAA:

Tumor-associated antigen

Tag:

SV40 large T antigen

TRAMP:

Transgenic adenocarcinoma of mouse prostate

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Acknowledgments

This work was supported by National Institutes of Health Grants R01 CA82419 and P50 DK065313. We are thankful for the technical assistance of Jenny Loveridge and Marvin Eng that was pivotal for the experiments described herein.

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Authors and Affiliations

  1. Departments of Urology and Pathology, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA

    Stephanie S. Tseng-Rogenski, Yilin C. Neeley & Arul M. Chinnaiyan

  2. Urology Division, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA

    Mohamed S. Arredouani, Bin Lu & Martin G. Sanda

Authors
  1. Stephanie S. Tseng-Rogenski
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  2. Mohamed S. Arredouani
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  3. Yilin C. Neeley
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  4. Bin Lu
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  5. Arul M. Chinnaiyan
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  6. Martin G. Sanda
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Correspondence to Martin G. Sanda.

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Tseng-Rogenski, S.S., Arredouani, M.S., Neeley, Y.C. et al. Fas-mediated T cell deletion potentiates tumor antigen-specific tolerance in a mouse model of prostate cancer. Cancer Immunol Immunother 57, 1357–1365 (2008). https://doi.org/10.1007/s00262-008-0471-z

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  • DOI: https://doi.org/10.1007/s00262-008-0471-z

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