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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-04

AUTHORS

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, Ryan T Sowell, Kimberly S Schluns, Richard E Davis, Patrick Hwu, Willem W Overwijk

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. More... »

PAGES

465

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nm.3105

DOI

http://dx.doi.org/10.1038/nm.3105

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008050192

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23455713


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