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Clinical Trial
. 2011;2011:249281.
doi: 10.1155/2011/249281. Epub 2011 Sep 28.

Dendritic Cell-Based Vaccines Positively Impact Natural Killer and Regulatory T Cells in Hepatocellular Carcinoma Patients

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Free PMC article
Clinical Trial

Dendritic Cell-Based Vaccines Positively Impact Natural Killer and Regulatory T Cells in Hepatocellular Carcinoma Patients

Sarah M Bray et al. Clin Dev Immunol. .
Free PMC article

Abstract

Immunotherapy of cancer must promote antitumor effector cells for tumor eradication as well as counteract immunoregulatory mechanisms which inhibit effectors. Immunologic therapies of cancer are showing promise, including dendritic cell-(DC-) based strategies. DC are highly malleable antigen-presenting cells which can promote potent antitumor immunity as well as tolerance, depending on the environmental signals received. Previously, we tested a peptide-pulsed DC vaccine to promote Alpha-fetoprotein (AFP-) specific anti-tumor immunity in patients with hepatocellular carcinoma (HCC), and reported on the CD8+ T cell responses induced by this vaccine and the clinical trial results. Here, we show that the peptide-loaded DC enhanced NK cell activation and decreased regulatory T cells (Treg) frequencies in vaccinated HCC patients. We also extend these data by testing several forms of DC vaccines in vitro to determine the impact of antigen loading and maturation signals on both NK cells and Treg from healthy donors and HCC patients.

Figures

Figure 1
Figure 1
CD69 and CD25 expression on CD56loCD16+ and CD56hiCD16 NK cells. Phenotyping of NK cells from patients who received the AFP pep/DC vaccine, showing longitudinal changes. “Pre” denotes PBMC from time point 0. DC vaccines were delivered (after blood draws) on days 0, 14, and 28. “Post” denotes PBMC from postvaccine administration at time points available in the remaining batched PBMC. Patient A1 tested at days 35 and 56 (7 days and 28 days after the third vaccine); pt B2 at d28, 56, and 112; pt B5 at d14 and 28; pt B8 and d14 and 112, pt A4 at d14. CD69 and CD25 markers (by MFI) are shown for both NK cell subsets. Percent positivity is shown in Supplementary Figure  2. One-tail t-test P values are: CD56loCD16+CD69 MFI: pre to post 1: 0.05; pre to post 2: 0.03; post 1 to post 2: 0.16; all other values higher and not significant (n.s.). CD56hiCD16CD69 MFI: pre to post 1: 0.07, all other values higher and n.s. CD56loCD16+CD25 MFI: pre to post 1: 0.05, pre to post 2: 0.11, post 1 to post 2: 0.12, all other values higher and n.s. CD56loCD16CD25 MFI: pre to post 1: 0.04, pre to post 2: 0.15, all other values higher and n.s.
Figure 2
Figure 2
FOXP3 expression in CD4+CD3+CD25hi (Treg) cells. Phenotyping of Treg cells from patients who received the pep/DC vaccine, showing longitudinal changes. “Pre” denotes PBMC from time point 0. “Post” denotes PBMC from postvaccine administration at time points available. Patient A1 tested at days 35 and 56; pt B2 at d28, 56, and 112; pt B5 at d14 and 28; pt B8 and d14 and 112, pt A4 at d14. (a) FOXP3 assessed intracellularly in CD3+CD4+CD25hi cells, showing MFI, or (b) % positivity. One-tail t-test P values are: FOXP3 MFI: pre to post 1: 0.09, pre to post 2: 0.07, post 1 to post 2: 0.17; all other values higher and n.s. FOXP3 percent positive: pre to post 1: 0.03; pre to post 2: 0.10; all other values higher and n.s.
Figure 3
Figure 3
CD69 expression on healthy donor CD56hi and CD56loCD16+ NK cells. Phenotyping of NK cells from HD PBMC after 48 hr coculture with different DC groups, showing CD69 upregulation on the (a) CD56loCD16+ and (b) CD56hiCD16 subsets for three HD.
Figure 4
Figure 4
CD69 expression on HCC patient NK cells. Phenotyping of NK cells from HCC patients after 48 hr coculture with different groups of DC, showing CD69 upregulation on CD56hiCD16 and CD56loCD16+ subtypes, by MFI (a) and percent positivity (b).
Figure 5
Figure 5
Treg cell responses to DC coculture. HD (a) and HCC patient (b, c, and d) CD4+ T cells were cocultured with differentially treated DC. The FOXP3 expression in CD3+/CD4+/CD25hi cells is shown in (a) as MFI (left), percent positive (middle). The right group is the frequency of total activated (CD25+) CD4+ T cells. The FOXP3 MFI in Treg in HCC patients is shown in (b). The percent CD3+/CD4+/CD25hi/FOXP3+ Treg in HCC patients is shown in (c). The overall frequency of activated CD4+ T cells is shown in (d) (% CD3+/CD4+/CD25+ cells).
Figure 6
Figure 6
Luminex results: production of chemokines and cytokines. Graphs are grouped according to scale of cytokine production and function. (a) IFN-γ, IP-10, TNF-α, and IL-2 production after CD4+ DC coculture. (b) MCP-1 and IL-5 production after CD4+ DC co-culture.

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