TY - JOUR
T1 - Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response
AU - Ercolini, Anne M.
AU - Ladle, Brian H.
AU - Manning, Elizabeth A.
AU - Pfannenstiel, Lukas W.
AU - Armstrong, Todd D.
AU - Machiels, Jean Pascal H.
AU - Bieler, Joan G.
AU - Emens, Leisha A.
AU - Reilly, R. Todd
AU - Jaffee, Elizabeth M.
PY - 2005/5/16
Y1 - 2005/5/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=21144454780&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=21144454780&partnerID=8YFLogxK
U2 - 10.1084/jem.20042167
DO - 10.1084/jem.20042167
M3 - Article
C2 - 15883172
AN - SCOPUS:21144454780
SN - 0022-1007
VL - 201
SP - 1591
EP - 1602
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -