The Journal of Experimental Medicine
Avanti Polar Lipids
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Published online 9 May 2005 doi:10.1084/jem.20042167
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 10, 1591-1602
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ARTICLE

 Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response

Anne M. Ercolini1,2,3, Brian H. Ladle1,2,4, Elizabeth A. Manning1,2,4, Lukas W. Pfannenstiel1,2,5, Todd D. Armstrong1,2, Jean-Pascal H. Machiels1,2, Joan G. Bieler6, Leisha A. Emens1,2, R. Todd Reilly1,2, and Elizabeth M. Jaffee1,2,3,4,5,6

1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21231
2 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231
3 Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21231
4 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231
5 Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231
6 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231

CORRESPONDENCE Elizabeth M. Jaffee: ejaffee{at}jhmi.edu

A major barrier to successful antitumor vaccination is tolerance of high-avidity T cells specific to tumor antigens. In keeping with this notion, HER-2/neu (neu)-targeted vaccines, which raise strong CD8+ T cell responses to a dominant peptide (RNEU420-429) in WT FVB/N mice and protect them from a neu-expressing tumor challenge, fail to do so in MMTV-neu (neu-N) transgenic mice. However, treatment of neu-N mice with vaccine and cyclophosphamide-containing chemotherapy resulted in tumor protection in a proportion of mice. This effect was specifically abrogated by the transfer of neu-N–derived CD4+CD25+ T cells. RNEU420-429-specific CD8+ T cells were identified only in neu-N mice given vaccine and cyclophosphamide chemotherapy which rejected tumor challenge. Tetramer-binding studies demonstrated that cyclophosphamide pretreatment allowed the activation of high-avidity RNEU420-429-specific CD8+ T cells comparable to those generated from vaccinated FVB/N mice. Cyclophosphamide seemed to inhibit regulatory T (T reg) cells by selectively depleting the cycling population of CD4+CD25+ T cells in neu-N mice. These findings demonstrate that neu-N mice possess latent pools of high-avidity neu-specific CD8+ T cells that can be recruited to produce an effective antitumor response if T reg cells are blocked or removed by using approaches such as administration of cyclophosphamide before vaccination.

Abbreviations used: BrdU, bromodeoxyuridine; Dox, doxorubicin; ICS, intracellular cytokine stain; koff, dissociation rate constant; neu, HER-2/neu; neu-N, MMTV-HER-2/neu transgenic mice; T reg, regulatory T.

A.M. Ercolini and B.H. Ladle contributed equally to this work.


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