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Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion

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Abstract

To understand why cancer vaccine–induced T cells often do not eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund's adjuvant (peptide/IFA), which is commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific CD8+ T cells, which accumulated not in tumors but rather at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, interferon-γ (IFN-γ)- and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of CD40-specific antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination-site sequestration. A nonpersisting vaccine formulation shifted T cell localization toward tumors, inducing superior antitumor activity while reducing systemic T cell dysfunction and promoting memory formation. These data show that persisting vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.

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Figure 1: Vaccination with gp100/IFA induces CD8+ T cell priming and hyporesponsiveness.
Figure 2: Vaccination with gp100/IFA induces chronic antigen presentation and T cell sequestration.
Figure 3: Vaccination-induced CD8+ T cell apoptosis at the vaccination site is driven by antigen and IFN-γ and requires host FasL.
Figure 4: T cell sequestration and deletion is overcome by vaccination with a short-lived, water-based vaccine formulation.
Figure 5: Vaccination with a short-lived, water-based vaccine formulation allows T cell localization to tumors.
Figure 6: Pmel-1 T cell phenotype after vaccination.

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  • 27 September 2013

     In the version of this article initially published, the author list omitted coauthor Ryan T. Sowell and his contribution. The author list and author contributions have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors thank G. Lizee, N. Martin-Orozco and J. Khalili for their helpful comments on this manuscript. This work was supported by the National Institutes of Health (NIH) grants R01 1CA143077 (W.W.O.) and P01 CA128913 (P.H. and W.W.O.) and a Melanoma Research Alliance Established Investigator Award (W.W.O.).

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Contributions

Y.H. designed and performed experiments and wrote the manuscript. Z.D., N.J., Y.Y., M.A.M., X.-F.H., N.R.G., G.N., S.M.D.-E., W.P., C.L. and Y.L. performed experiments. R.T.S. and K.S.S. constructed VSV.gp100. B.R. and P.H. provided the v-effLuc-GFP–expressing retroviral construct and imaging expertise. Z.W., W.M. and R.E.D. performed and analyzed gene expression arrays. W.W.O. conceived the study and wrote the manuscript.

Corresponding author

Correspondence to Willem W Overwijk.

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Hailemichael, Y., Dai, Z., Jaffarzad, N. et al. Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nat Med 19, 465–472 (2013). https://doi.org/10.1038/nm.3105

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