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

Yared Hailemichael, Zhimin Dai, Nina Jaffarzad, Yang Ye, Miguel A. Medina, Xue Fei Huang, Stephanie M. Dorta-Estremera, Nathaniel R. Greeley, Giovanni Nitti, Weiyi Peng, Chengwen Liu, Yanyan Lou, Zhiqiang Wang, Wencai Ma, Brian Rabinovich, Kimberly S. Schluns, Richard E. Davis, Patrick Hwu, Willem W. Overwijk

Research output: Contribution to journalArticle

253 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)465-472
Number of pages8
JournalNature Medicine
Volume19
Issue number4
DOIs
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Hailemichael, Y., Dai, Z., Jaffarzad, N., Ye, Y., Medina, M. A., Huang, X. F., Dorta-Estremera, S. M., Greeley, N. R., Nitti, G., Peng, W., Liu, C., Lou, Y., Wang, Z., Ma, W., Rabinovich, B., Schluns, K. S., Davis, R. E., Hwu, P., & Overwijk, W. W. (2013). Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nature Medicine, 19(4), 465-472. https://doi.org/10.1038/nm.3105