Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 1702K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ercolini, A. M. Articles by Jaffee, E. M. Search for Related Content PubMed PubMed Citation Articles by Ercolini, A. M. Articles by Jaffee, E. M. Pubmed/NCBI databases Gene Compound via MeSH Substance via MeSH Hazardous Substances DB CYCLOPHOSPHAMIDE Social Bookmarking                            What's this?

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 (RNEU_420-429) 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. RNEU_420-429-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 RNEU_420-429-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.

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Kohlmeyer, J., Cron, M., Landsberg, J., Bald, T., Renn, M., Mikus, S., Bondong, S., Wikasari, D., Gaffal, E., Hartmann, G., Tuting, T. (2009). Complete Regression of Advanced Primary and Metastatic Mouse Melanomas following Combination Chemoimmunotherapy. Cancer Res. 69: 6265-6274 [Abstract] [Full Text]  
• Wei, H., Wang, S., Zhang, D., Hou, S., Qian, W., Li, B., Guo, H., Kou, G., He, J., Wang, H., Guo, Y. (2009). Targeted Delivery of Tumor Antigens to Activated Dendritic Cells via CD11c Molecules Induces Potent Antitumor Immunity in Mice. Clin. Cancer Res. 15: 4612-4621 [Abstract] [Full Text]  
• Hirschhorn-Cymerman, D., Rizzuto, G. A., Merghoub, T., Cohen, A. D., Avogadri, F., Lesokhin, A. M., Weinberg, A. D., Wolchok, J. D., Houghton, A. N. (2009). OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. JEM 206: 1103-1116 [Abstract] [Full Text]  
• Seavey, M. M., Maciag, P. C., Al-Rawi, N., Sewell, D., Paterson, Y. (2009). An Anti-Vascular Endothelial Growth Factor Receptor 2/Fetal Liver Kinase-1 Listeria monocytogenes Anti-Angiogenesis Cancer Vaccine for the Treatment of Primary and Metastatic Her-2/neu+ Breast Tumors in a Mouse Model. J. Immunol. 182: 5537-5546 [Abstract] [Full Text]  
• Lee, C.-H., Chiang, Y.-H., Chang, S.-E., Chong, C.-L., Cheng, B.-M., Roffler, S. R. (2009). Tumor-Localized Ligation of CD3 and CD28 with Systemic Regulatory T-Cell Depletion Induces Potent Innate and Adaptive Antitumor Responses. Clin. Cancer Res. 15: 2756-2766 [Abstract] [Full Text]  
• Pavelko, K. D., Hansen, M. J., Pease, L. R. (2009). CTL Activation Using the Natural Low-Affinity Epitope 222-229 from Tyrosinase-Related Protein 1 Leads to Tumor Rejection. Cancer Res. 69: 3114-3120 [Abstract] [Full Text]  
• Nicholaou, T., Ebert, L. M., Davis, I. D., McArthur, G. A., Jackson, H., Dimopoulos, N., Tan, B., Maraskovsky, E., Miloradovic, L., Hopkins, W., Pan, L., Venhaus, R., Hoffman, E. W., Chen, W., Cebon, J. (2009). Regulatory T-Cell-Mediated Attenuation of T-Cell Responses to the NY-ESO-1 ISCOMATRIX Vaccine in Patients with Advanced Malignant Melanoma. Clin. Cancer Res. 15: 2166-2173 [Abstract] [Full Text]  
• Seavey, M. M., Pan, Z.-K., Maciag, P. C., Wallecha, A., Rivera, S., Paterson, Y., Shahabi, V. (2009). A Novel Human Her-2/neu Chimeric Molecule Expressed by Listeria monocytogenes Can Elicit Potent HLA-A2 Restricted CD8-positive T cell Responses and Impact the Growth and Spread of Her-2/neu-positive Breast Tumors. Clin. Cancer Res. 15: 924-932 [Abstract] [Full Text]  
• Mukherjee, P., Basu, G. D., Tinder, T. L., Subramani, D. B., Bradley, J. M., Arefayene, M., Skaar, T., De Petris, G. (2009). Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition. J. Immunol. 182: 216-224 [Abstract] [Full Text]  
• Sloots, A., Mastini, C., Rohrbach, F., Weth, R., Curcio, C., Burkhardt, U., Jager, E., Forni, G., Cavallo, F., Wels, W. S. (2008). DNA Vaccines Targeting Tumor Antigens to B7 Molecules on Antigen-Presenting Cells Induce Protective Antitumor Immunity and Delay Onset of HER-2/Neu-Driven Mammary Carcinoma. Clin. Cancer Res. 14: 6933-6943 [Abstract] [Full Text]  
• Song, H., Shahverdi, K., Huso, D. L., Wang, Y., Fox, J. J., Hobbs, R. F., Gimi, B., Gabrielson, K. L., Pomper, M. G., Tsui, B. M., Bhujwalla, Z., Reilly, R. T., Sgouros, G. (2008). An Immunotolerant HER-2/neu Transgenic Mouse Model of Metastatic Breast Cancer. Clin. Cancer Res. 14: 6116-6124 [Abstract] [Full Text]  
• Sharma, S., Dominguez, A. L., Manrique, S. Z., Cavallo, F., Sakaguchi, S., Lustgarten, J. (2008). Systemic Targeting of CpG-ODN to the Tumor Microenvironment with Anti-neu-CpG Hybrid Molecule and T Regulatory Cell Depletion Induces Memory Responses in BALB-neuT Tolerant Mice. Cancer Res. 68: 7530-7540 [Abstract] [Full Text]  
• Quezada, S. A., Peggs, K. S., Simpson, T. R., Shen, Y., Littman, D. R., Allison, J. P. (2008). Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. JEM 205: 2125-2138 [Abstract] [Full Text]  
• Nishikawa, H., Kato, T., Hirayama, M., Orito, Y., Sato, E., Harada, N., Gnjatic, S., Old, L. J., Shiku, H. (2008). Regulatory T Cell-Resistant CD8+ T Cells Induced by Glucocorticoid-Induced Tumor Necrosis Factor Receptor Signaling. Cancer Res. 68: 5948-5954 [Abstract] [Full Text]  
• Gritzapis, A. D., Voutsas, I. F., Lekka, E., Tsavaris, N., Missitzis, I., Sotiropoulou, P., Perez, S., Papamichail, M., Baxevanis, C. N. (2008). Identification of a Novel Immunogenic HLA-A*0201-Binding Epitope of HER-2/neu with Potent Antitumor Properties. J. Immunol. 181: 146-154 [Abstract] [Full Text]  
• Lutsiak, M. E. C., Tagaya, Y., Adams, A. J., Schlom, J., Sabzevari, H. (2008). Tumor-Induced Impairment of TCR Signaling Results in Compromised Functionality of Tumor-Infiltrating Regulatory T Cells. J. Immunol. 180: 5871-5881 [Abstract] [Full Text]  
• Plesa, G., Snook, A. E., Waldman, S. A., Eisenlohr, L. C. (2008). Derivation and Fluidity of Acutely Induced Dysfunctional CD8+ T Cells. J. Immunol. 180: 5300-5308 [Abstract] [Full Text]  
• Castano, A. P., Mroz, P., Wu, M. X., Hamblin, M. R. (2008). Photodynamic therapy plus low-dose cyclophosphamide generates antitumor immunity in a mouse model. Proc. Natl. Acad. Sci. USA 105: 5495-5500 [Abstract] [Full Text]  
• Laheru, D., Lutz, E., Burke, J., Biedrzycki, B., Solt, S., Onners, B., Tartakovsky, I., Nemunaitis, J., Le, D., Sugar, E., Hege, K., Jaffee, E. (2008). Allogeneic Granulocyte Macrophage Colony-Stimulating Factor-Secreting Tumor Immunotherapy Alone or in Sequence with Cyclophosphamide for Metastatic Pancreatic Cancer: A Pilot Study of Safety, Feasibility, and Immune Activation. Clin. Cancer Res. 14: 1455-1463 [Abstract] [Full Text]  
• Degl'Innocenti, E., Grioni, M., Capuano, G., Jachetti, E., Freschi, M., Bertilaccio, M. T.S., Hess-Michelini, R., Doglioni, C., Bellone, M. (2008). Peripheral T-Cell Tolerance Associated with Prostate Cancer Is Independent from CD4+CD25+ Regulatory T Cells. Cancer Res. 68: 292-300 [Abstract] [Full Text]  
• Li, Y., Yee, C. (2008). IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes. Blood 111: 229-235 [Abstract] [Full Text]  
• Powell, D. J. Jr., Felipe-Silva, A., Merino, M. J., Ahmadzadeh, M., Allen, T., Levy, C., White, D. E., Mavroukakis, S., Kreitman, R. J., Rosenberg, S. A., Pastan, I. (2007). Administration of a CD25-Directed Immunotoxin, LMB-2, to Patients with Metastatic Melanoma Induces a Selective Partial Reduction in Regulatory T Cells In Vivo. J. Immunol. 179: 4919-4928 [Abstract] [Full Text]  
• Berraondo, P., Nouze, C., Preville, X., Ladant, D., Leclerc, C. (2007). Eradication of Large Tumors in Mice by a Tritherapy Targeting the Innate, Adaptive, and Regulatory Components of the Immune System. Cancer Res. 67: 8847-8855 [Abstract] [Full Text]  
• Stewart, T. J., Abrams, S. I. (2007). Altered Immune Function during Long-Term Host-Tumor Interactions Can Be Modulated to Retard Autochthonous Neoplastic Growth. J. Immunol. 179: 2851-2859 [Abstract] [Full Text]  
• Spadaro, M., Curcio, C., Varadhachary, A., Cavallo, F., Engelmayer, J., Blezinger, P., Pericle, F., Forni, G. (2007). Requirement for IFN-{gamma}, CD8+ T Lymphocytes, and NKT Cells in Talactoferrin-Induced Inhibition of neu+ Tumors. Cancer Res. 67: 6425-6432 [Abstract] [Full Text]  
• Zhang, P., Cote, A. L., de Vries, V. C., Usherwood, E. J., Turk, M. J. (2007). Induction of Postsurgical Tumor Immunity and T-Cell Memory by a Poorly Immunogenic Tumor. Cancer Res. 67: 6468-6476 [Abstract] [Full Text]  
• Manning, E. A., Ullman, J. G.M., Leatherman, J. M., Asquith, J. M., Hansen, T. R., Armstrong, T. D., Hicklin, D. J., Jaffee, E. M., Emens, L. A. (2007). A Vascular Endothelial Growth Factor Receptor-2 Inhibitor Enhances Antitumor Immunity through an Immune-Based Mechanism. Clin. Cancer Res. 13: 3951-3959 [Abstract] [Full Text]  
• Nava-Parada, P., Forni, G., Knutson, K. L., Pease, L. R., Celis, E. (2007). Peptide Vaccine Given with a Toll-Like Receptor Agonist Is Effective for the Treatment and Prevention of Spontaneous Breast Tumors. Cancer Res. 67: 1326-1334 [Abstract] [Full Text]  
• Bracci, L., Moschella, F., Sestili, P., La Sorsa, V., Valentini, M., Canini, I., Baccarini, S., Maccari, S., Ramoni, C., Belardelli, F., Proietti, E. (2007). Cyclophosphamide Enhances the Antitumor Efficacy of Adoptively Transferred Immune Cells through the Induction of Cytokine Expression, B-Cell and T-Cell Homeostatic Proliferation, and Specific Tumor Infiltration. Clin. Cancer Res. 13: 644-653 [Abstract] [Full Text]  
• Charalambous, A., Oks, M., Nchinda, G., Yamazaki, S., Steinman, R. M. (2006). Dendritic Cell Targeting of Survivin Protein in a Xenogeneic Form Elicits Strong CD4+ T Cell Immunity to Mouse Survivin. J. Immunol. 177: 8410-8421 [Abstract] [Full Text]  
• Rolla, S., Nicolo, C., Malinarich, S., Orsini, M., Forni, G., Cavallo, F., Ria, F. (2006). Distinct and Non-Overlapping T Cell Receptor Repertoires Expanded by DNA Vaccination in Wild-Type and HER-2 Transgenic BALB/c Mice. J. Immunol. 177: 7626-7633 [Abstract] [Full Text]  
• Ambrosino, E., Spadaro, M., Iezzi, M., Curcio, C., Forni, G., Musiani, P., Wei, W.-Z., Cavallo, F. (2006). Immunosurveillance of erbb2 carcinogenesis in transgenic mice is concealed by a dominant regulatory T-cell self-tolerance.. Cancer Res. 66: 7734-7740 [Abstract] [Full Text]  
• Singh, R., Paterson, Y. (2006). Vaccination Strategy Determines the Emergence and Dominance of CD8+ T-Cell Epitopes in a FVB/N Rat HER-2/neu Mouse Model of Breast Cancer.. Cancer Res. 66: 7748-7757 [Abstract] [Full Text]  
• Knutson, K. L., Lu, H., Stone, B., Reiman, J. M., Behrens, M. D., Prosperi, C. M., Gad, E. A., Smorlesi, A., Disis, M. L. (2006). Immunoediting of Cancers May Lead to Epithelial to Mesenchymal Transition. J. Immunol. 177: 1526-1533 [Abstract] [Full Text]  
• Beyer, M., Schultze, J. L. (2006). Regulatory T cells in cancer. Blood 108: 804-811 [Abstract] [Full Text]  
• Wang, W., Epler, J., Salazar, L. G., Riddell, S. R. (2006). Recognition of Breast Cancer Cells by CD8+ Cytotoxic T-Cell Clones Specific for NY-BR-1.. Cancer Res. 66: 6826-6833 [Abstract] [Full Text]  
• Knutson, K. L., Dang, Y., Lu, H., Lukas, J., Almand, B., Gad, E., Azeke, E., Disis, M. L. (2006). IL-2 Immunotoxin Therapy Modulates Tumor-Associated Regulatory T Cells and Leads to Lasting Immune-Mediated Rejection of Breast Cancers in neu-Transgenic Mice. J. Immunol. 177: 84-91 [Abstract] [Full Text]  
• Pannellini, T., Spadaro, M., Di Carlo, E., Ambrosino, E., Iezzi, M., Amici, A., Lollini, P. L., Forni, G., Cavallo, F., Musiani, P. (2006). Timely DNA Vaccine Combined with Systemic IL-12 Prevents Parotid Carcinomas before a Dominant-Negative p53 Makes Their Growth Independent of HER-2/neu Expression.. J. Immunol. 176: 7695-7703 [Abstract] [Full Text]  
• Eguchi, J., Hatano, M., Nishimura, F., Zhu, X., Dusak, J. E., Sato, H., Pollack, I. F., Storkus, W. J., Okada, H. (2006). Identification of Interleukin-13 Receptor {alpha}2 Peptide Analogues Capable of Inducing Improved Antiglioma CTL Responses. Cancer Res. 66: 5883-5891 [Abstract] [Full Text]  
• Condomines, M., Quittet, P., Lu, Z.-Y., Nadal, L., Latry, P., Lopez, E., Baudard, M., Requirand, G., Duperray, C., Schved, J.-F., Rossi, J.-F., Tarte, K., Klein, B. (2006). Functional Regulatory T Cells Are Collected in Stem Cell Autografts by Mobilization with High-Dose Cyclophosphamide and Granulocyte Colony-Stimulating Factor.. J. Immunol. 176: 6631-6639 [Abstract] [Full Text]  
• Murata, S., Ladle, B. H., Kim, P. S., Lutz, E. R., Wolpoe, M. E., Ivie, S. E., Smith, H. M., Armstrong, T. D., Emens, L. A., Jaffee, E. M., Reilly, R. T. (2006). OX40 Costimulation Synergizes with GM-CSF Whole-Cell Vaccination to Overcome Established CD8+ T Cell Tolerance to an Endogenous Tumor Antigen. J. Immunol. 176: 974-983 [Abstract] [Full Text]  
• Laheru, D. A., Pardoll, D. M., Jaffee, E. M. (2005). Genes to vaccines for immunotherapy: how the molecular biology revolution has influenced cancer immunology. Molecular Cancer Therapeutics 4: 1645-1652 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS