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Fusions of Dendritic Cells with Breast Carcinoma Stimulate the Expansion of Regulatory T Cells while Concomitant Exposure to IL-12, CpG Oligodeoxynucleotides, and Anti-CD3/CD28 Promotes the Expansion of Activated Tumor Reactive Cells¹

Baldev Vasir^*, Zekui Wu^*, Keith Crawford, Jacalyn Rosenblatt, Corrine Zarwan, Adam Bissonnette^*, Donald Kufe^* and David Avigan^2,

^* Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, Center for Molecular Orthopaedics, Brigham & Women’s Hospital, and Beth Israel Deaconess Medical Center, Boston, MA 02115

Vaccination of patients with dendritic cell (DC)/breast carcinoma fusions stimulated antitumor immune responses in a majority of patients with metastatic disease but only a subset demonstrate evidence of tumor regression. To define the factors that limit vaccine efficacy, we examined the biological characteristics of DC/breast carcinoma fusions as APCs and the nature of the vaccine-mediated T cell response. We demonstrate that fusion of DCs with breast carcinoma cells up-regulates expression of costimulatory and maturation markers and results in high levels of expression of IL-12 consistent with their role as activated APCs. Fusion cells also express the chemokine receptor CCR7, consistent with their ability to migrate to the draining lymph node. However, DC/breast cancer fusions stimulate a mixed T cell response characterized by the expansion of both activated and regulatory T cell populations, the latter of which is characterized by expression of CTLA-4, FOXP3, IL-10, and the suppression of T cell responses. Our results demonstrate that IL-12, IL-18, and TLR 9 agonist CpG oligodeoxynucleotides reduce the level of fusion-mediated regulatory T cell expansion. Our results also demonstrate that sequential stimulation with DC/breast carcinoma fusions and anti-CD3/CD28 results in the marked expansion of activated tumor-specific T cells. These findings suggest that DC/breast carcinoma fusions are effective APCs, but stimulate inhibitory T cells that limit vaccine efficacy. In contrast, exposure to TLR agonists, stimulatory cytokines, and anti-CD3/CD28 enhances vaccine efficacy by limiting the regulatory T cell response and promoting expansion of activated effector cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Department of Defense Grant DAMD17-03-1-0487 and in part by Dana-Farber Cancer Institute/Harvard Cancer Center Ovarian Cancer Specialized Program of Research Excellence Grant P50CA105009-04.

² Address correspondence and reprint requests to Dr. David Avigan, Hematologic Malignancy/Bone Marrow Transplant Program, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, KS-135, Boston, MA 02115. E-mail address: davigan{at}bidmc.harvard.edu

³ Abbreviations used in this paper: DC, dendritic cell; ODN, oligodeoxynucleotide; PEG, polyethylene glycol; SI, stimulation index; CBA, cytometric bead array; GITR, glucocorticoid-induced TNF receptor.