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 cells.
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.
Vasir
Baldev
B
Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, Brigham & Women's Hospital, Boston, MA 02115, USA.
Wu
Zekui
Z
Crawford
Keith
K
Rosenblatt
Jacalyn
J
Zarwan
Corrine
C
Bissonnette
Adam
A
Kufe
Donald
D
Avigan
David
D
D000906:Antibodies / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D002459:Cell Fusion; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000276:immunology; D018396:Mucin-1 / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology*; D010641:Phenotype; D011485:Protein Binding; D054400:Receptors, CCR7 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D000906:Antibodies; C515370:CCR7 protein, human; D018106:CD28 Antigens; D017252:CD3 Complex; C060192:MUC1 protein, human; D018396:Mucin-1; D009841:Oligonucleotides; D054400:Receptors, CCR7; D016753:Interleukin-10; D018664:Interleukin-12