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

Anne M. Ercolini, Brian H. Ladle, Elizabeth A. Manning, Lukas W. Pfannenstiel, Todd D. Armstrong, Jean Pascal H. Machiels, Joan G. Bieler, Leisha A. Emens, R. Todd Reilly, Elizabeth M. Jaffee

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355 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1591-1602
Number of pages12
JournalJournal of Experimental Medicine
Issue number10
StatePublished - May 16 2005
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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