This project analyzes the ability of a Saccharomyces cerevisiae vector containing the transgene encoding CEA (yeast-CEA) to activate human dendritic cells (DCs) and stimulate CEA-specific T-cell responses. We demonstrate for the first time that treatment with yeast-CEA can activate human DCs, resulting in increases in surface expression of CD80, CD83, CD54, CD58, and MHC class II, and increased production by DCs of IL-12p70, TNF-alpha, IFN-gamma, IL-8, IL-2, IL-13, IL-10, and IL-1beta. We also show that human DCs treated with yeast-CEA can activate CEA-specific T-cell lines and can act as antigen-presenting cells (APCs) to generate CEA-specific T-cell lines capable of lysing CEA+ human tumor cells. Gene expression profiles of human DCs treated with yeast-CEA show increased expression of numerous genes involved in the production of chemokines and cytokines and their receptors, and genes related to antigen uptake, antigen presentation, and signal transduction. Enhanced functionality of CD4+CD25highFoxP3+ regulatory T cells in the peripheral blood of patients with prostate cancer. CD4+CD25highFoxP3+ regulatory T cells (Treg) have been shown to inhibit the activation and function of T cells that participate in antigen-specific immune responses. Higher levels of Tregs have been reported in the peripheral blood of patients with several types of tumors. In this study, we investigated the number and functionality of CD4+CD25highFoxP3+ Tregs in patients with prostate cancer (PCa), and their potential role in inhibiting antitumor immune responses. Levels of Tregs in the peripheral blood of healthy donors and patients with biochemically progressive, localized, and metastatic PCa were each measured by flow cytometry. The functional activity of Tregs was determined by their ability to suppress the proliferation of CD4+CD25- T cells. Data were analyzed using Wilcoxon rank sum test and unpaired Students t test. Although levels of Tregs in the peripheral blood of patients with PCa were not significantly higher than those in healthy donors, Tregs in patients with PCa had significantly greater suppressive functionality than Tregs from healthy donors (P less than 0.05). Additionally, there was a direct correlation between the serum levels of prostaglandin E2 and Treg functionality in patients with localized PCa, using Pearsons product-moment correlation coefficient (R). These findings further show the potential importance of Tregs in modifying immune responses in patients with PCa. Although longer studies are necessary to confirm these findings, these studies also show for the first time the differences in Treg populations in patients with various stages of PCa, and thus, provide a basis for determining which PCa patient populations are best suited for immunotherapy trials involving the inhibition of Tregs.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Kim, Peter S; Jochems, Caroline; Grenga, Italia et al. (2014) Pan-Bcl-2 inhibitor, GX15-070 (obatoclax), decreases human T regulatory lymphocytes while preserving effector T lymphocytes: a rationale for its use in combination immunotherapy. J Immunol 192:2622-33
Gameiro, Sofia R; Jammeh, Momodou L; Wattenberg, Max M et al. (2014) Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget 5:403-16
Schlom, Jeffrey; Hodge, James W; Palena, Claudia et al. (2014) Therapeutic cancer vaccines. Adv Cancer Res 121:67-124
Jochems, Caroline; Tucker, Jo A; Tsang, Kwong-Yok et al. (2014) A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates. Cancer Immunol Immunother 63:407-18
Gulley, James L; Madan, Ravi A; Tsang, Kwong Y et al. (2014) Immune impact induced by PROSTVAC (PSA-TRICOM), a therapeutic vaccine for prostate cancer. Cancer Immunol Res 2:133-41
Farsaci, Benedetto; Jochems, Caroline; Grenga, Italia et al. (2014) Identification by digital immunohistochemistry of intratumoral changes of immune infiltrates after vaccine in the absence of modifications of PBMC immune cell subsets. Int J Cancer 135:862-70
Takai, Shinji; Schlom, Jeffrey; Tucker, Joanne et al. (2013) Inhibition of TGF-?1 signaling promotes central memory T cell differentiation. J Immunol 191:2299-307
Huen, Ngar-Yee; Pang, Alan Lap-Yin; Tucker, Jo A et al. (2013) Up-regulation of proliferative and migratory genes in regulatory T cells from patients with metastatic castration-resistant prostate cancer. Int J Cancer 133:373-82
Gulley, James L; Heery, Christopher R; Madan, Ravi A et al. (2013) Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer. Cancer Immunol Immunother 62:1521-31
Vergati, Matteo; Schlom, Jeffrey; Tsang, Kwong Y (2011) The consequence of immune suppressive cells in the use of therapeutic cancer vaccines and their importance in immune monitoring. J Biomed Biotechnol 2011:182413

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