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Rapid accumulation of adoptively transferred CD8+ T cells at the tumor site is associated with long-term control of SV40 T antigen-induced tumors

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Abstract

We previously established a model to study CD8+ T cell (TCD8)-based adoptive immunotherapy of cancer using line SV11 mice that develop choroid plexus tumors in the brain due to transgenic expression of Simian Virus 40 large T antigen (Tag). These mice are tolerant to the three dominant TCD8-recognized Tag epitopes I, II/III and IV. However, adoptive transfer of spleen cells from naïve C57BL/6 (B6) mice prolongs SV11 survival following TCD8 priming against the endogenous Tag epitope IV. In addition, survival of SV11 mice is dramatically increased following transfer of lymphocytes from Tag-immune B6 mice. In the current study, we compared the kinetics and magnitude of Tag-specific TCD8 accumulation at the tumor site following adoptive transfer with a high dose of either Tag-immune or naïve donor cells or decreasing doses of Tag-immune lymphocytes. Following adoptive transfer of Tag-immune cells, epitope I- and IV-specific TCD8 accumulated to high levels in the brain of SV11 mice, peaking at 5–7 days, while epitope IV-specific TCD8 derived from naïve donors required three weeks to achieve peak levels. A similar delay in the peak of epitope IV-specific TCD8 accumulation was observed when tenfold fewer Tag-immune donor cells were administered, reducing control of tumor progression. These results suggest that efficient and prolonged control of established autochthonous tumors is associated with high-level early accumulation of adoptively transferred T cells. We also provide evidence that although multiple specificities are represented in the Tag immune donor lymphocytes, epitope IV-specific donor TCD8 play a predominant role in control of tumor growth.

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Acknowledgments

We thank Melanie Epler and Jeremy Haley for excellent technical support and Nate Sheaffer from the Flow Cytometric Core Facility of the M.S. Hershey Medical Center for assistance with flow cytometry. This work was supported by CA25000 from the National Cancer Institute/National Institutes of Health.

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  1. Jodi L. Yorty

    Present address: Department of Biology, Elizabethtown College, One Alpha Drive, Elizabethtown, PA, 17022, USA

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  1. Department of Microbiology and Immunology, H107, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA

    Jodi L. Yorty, Satvir S. Tevethia & Todd D. Schell

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  1. Jodi L. Yorty
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Correspondence to Todd D. Schell.

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Yorty, J.L., Tevethia, S.S. & Schell, T.D. Rapid accumulation of adoptively transferred CD8+ T cells at the tumor site is associated with long-term control of SV40 T antigen-induced tumors. Cancer Immunol Immunother 57, 883–895 (2008). https://doi.org/10.1007/s00262-007-0424-y

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