Tumor-Derived α-Fetoprotein Impairs the Differentiation and T Cell Stimulatory Activity of Human Dendritic Cells

Pardee, Angela D.; Shi, Jian; Butterfield, Lisa H.

doi:10.4049/jimmunol.1400725

Cited by 87 publications

(94 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A series of studies have proposed that AFP is able to regulate other immune cells. Tumor-derived AFP causes suppression of T lymphocyte responses (44). Here, we intended to understand the effect of fetus-derived AFP on B cells, in particular, how AFP impacts on their capacity to produce IL-10.…”

Section: Discussionmentioning

confidence: 99%

Maternal and Fetal Mechanisms of B Cell Regulation during Pregnancy: Human Chorionic Gonadotropin Stimulates B Cells to Produce IL-10 While Alpha-Fetoprotein Drives Them into Apoptosis

et al. 2016

View full text Add to dashboard Cite

Maternal immune tolerance toward the fetus is an essential requisite for pregnancy. While T cell functions are well documented, little is known about the participation of B cells. We have previously suggested that IL-10-producing B cells are involved in pregnancy tolerance in mice and humans. By employing murine and human systems, we report now that fetal trophoblasts positively regulate the generation of IL-10-producing B cells. We next studied the participation of hormones produced by the placenta as well as the fetal protein alpha-fetoprotein (AFP) in B cell modulation. Human chorionic gonadotropin (hCG), but not progesterone, estrogen, or a combination of both, was able to promote changes in B cell phenotype and boost their IL-10 production, which was abolished after blocking hCG. The hCG-induced B cell phenotype was not associated with augmented galactosylation, sialylation, or fucosylation of IgG subclasses in their Fc. In vitro, hCG induced the synthesis of asymmetrically glycosylated antibodies in their Fab region. Interestingly, AFP had dual effects depending on the concentration. At concentrations corresponding to maternal serum levels, it did not modify the phenotype or IL-10 secretion of B cells. At fetal concentrations, however, AFP was able to drive B cells into apoptosis, which may indicate a protective mechanism to avoid maternal B cells to reach the fetus. Our data suggest that the fetus secrete factors that promote a pregnancy-friendly B cell phenotype, unraveling interesting aspects of B cell function, and modulation by pregnancy hormones and fetal proteins.

show abstract

Section: Discussionmentioning

confidence: 99%

Maternal and Fetal Mechanisms of B Cell Regulation during Pregnancy: Human Chorionic Gonadotropin Stimulates B Cells to Produce IL-10 While Alpha-Fetoprotein Drives Them into Apoptosis

et al. 2016

View full text Add to dashboard Cite

show abstract

“…We have observed that uptake of AFP causes morphologic change in monocyte-derived DC (DC) and impairs their differentiation [3]. The effects of tumor-derived AFP (tAFP) are more potent than those of cord blood-derived “normal” AFP (nAFP).…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular cancer-derived alpha fetoprotein uptake reduces CD1 molecules on monocyte-derived dendritic cells

Song

Santos

et al. 2019

Cellular Immunology

Self Cite

View full text Add to dashboard Cite

Alpha fetoprotein (AFP) is produced by over 50% of hepatocellular carcinomas (HCC). Uptake of tumor-derived AFP (tAFP) can impair activity of human dendritic cells (DC). The expression pattern of the lipid antigen presenting genes from the CD1 family is reduced in AFP-treated monocyte-derived DC. Surface CD1 family proteins, particularly CD1d, were reduced in AFP-exposed DC (by both normal cord blood-derived AFP (nAFP) and tAFP). NKT cells recognize lipid antigens presented by CD1d molecules. They play an important role in connecting the innate and adaptive immune systems, and in anti-tumor immunity. We hypothesized that AFP might impair the ability of DC to stimulate natural killer T (NKT) cells. No significant impact of AFP was observed on NKT cell stimulation. By examining secreted cytokines, we observed non-significant AFP-induced changes in several secreted proteins. These data indicate that AFP downregulates CD1 molecules on DC, but the impact on NKT cell activations is minimal.

show abstract

“…In HCC patients exhibiting high levels of serum tAFP, we have observed a lower ratio of myeloid-to-plasmacytoid circulating DC compared to patients with low serum AFP levels and healthy donors [42]. To test the possible effect of nAFP or tAFP on DC differentiation, peripheral blood monocytes were cultured in vitro in the presence of nAFP or HCC-derived tAFP, and DC phenotype and function was assessed [42].…”

Section: Discussionmentioning

confidence: 99%

“…To test the possible effect of nAFP or tAFP on DC differentiation, peripheral blood monocytes were cultured in vitro in the presence of nAFP or HCC-derived tAFP, and DC phenotype and function was assessed [42]. Although the nAFP and tAFP isoforms only differ at one glycosylation site, low levels of tAFP significantly inhibited DC differentiation while nAFP had a more modest impact.…”

Section: Discussionmentioning

confidence: 99%

“…The suppressive activity was not associated with a co-purifying (or contaminating) protein, as shown by protein mass spectroscopy. Enzymatic elimination of fucose groups as well as of all sugar groups attached to tAFP did not eliminate the suppressive activity [42]. These data reveal the unique ability of tAFP to serve as a chaperone protein for a non-protein/non-glycan LMW molecule which functions cooperatively with AFP protein to impair DC differentiation and function.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Lessons learned from cancer vaccine trials and target antigen choice

Butterfield

2016

Cancer Immunol Immunother

Self Cite

View full text Add to dashboard Cite

A wide variety of tumor antigens have been targeted in cancer immunotherapy studies. Traditionally, the focus has been on commonly over-expressed antigens shared across many patients and/or tumor types. As the field has progressed, the identity of human tumor rejection antigens has broadened. Immunologic monitoring of clinical trials has slowly elucidated candidate biomarkers of immune response and clinical response, and conversely, of immune dysfunction and suppression. We have utilized MART-1/Melan-A in our melanoma studies, and observed a high frequency of immune responses and several significant clinical responses in patients vaccinated with this melanosomal protein. Alpha-fetoprotein (AFP) is a shared, over-expressed tumor antigen and secreted glycoprotein that we have tested in hepatocellular cancer (HCC) vaccines. Our recent studies have identified immune suppressive and immune skewing activities of this antigen. The choice of target antigen and its form can have unexpected effects.

show abstract

Tumor-Derived α-Fetoprotein Impairs the Differentiation and T Cell Stimulatory Activity of Human Dendritic Cells

Cited by 87 publications

References 41 publications

Maternal and Fetal Mechanisms of B Cell Regulation during Pregnancy: Human Chorionic Gonadotropin Stimulates B Cells to Produce IL-10 While Alpha-Fetoprotein Drives Them into Apoptosis

Maternal and Fetal Mechanisms of B Cell Regulation during Pregnancy: Human Chorionic Gonadotropin Stimulates B Cells to Produce IL-10 While Alpha-Fetoprotein Drives Them into Apoptosis

Hepatocellular cancer-derived alpha fetoprotein uptake reduces CD1 molecules on monocyte-derived dendritic cells

Lessons learned from cancer vaccine trials and target antigen choice

Contact Info

Product

Resources

About