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

Abstract

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.

AFP-Inhibiting Fragments for Drug Delivery: The Promise and Challenges of Targeting Therapeutics to Cancers

“…In some cancers, full-length glycosylated AFP has immunosuppressive effects by stimulating cancer growth and directly activating MDSCs ( Pak, 2018a , b ). Moreover, tAFP significantly inhibits dendritic cell (DC) differentiation, thereby playing a critical role in immunosuppression ( Pardee et al, 2014 ; Li et al, 2019 ). Therefore, it is more suitable to use AIF than tAFP for manufacturing vaccines to prevent the initiation of cancer.…”

Immunomodulatory impact of α-fetoprotein

“…NKT cells are also prominent in the microvasculature of the liver and play essential roles in normal physiology [65]. Given the prominence of NKTs in the liver and their emerging role in cancer immunotherapy [66], our group also sought to better understand how AFP might regulate CD1d molecules on DCs, thereby limiting NKT cell function in vitro [67]. We found that both nAFP and tAFP led to significant downregulation of CD1d on DCs; however, this did not diminish their potential to stimulate NKT cells [67].…”

“…Given the prominence of NKTs in the liver and their emerging role in cancer immunotherapy [66], our group also sought to better understand how AFP might regulate CD1d molecules on DCs, thereby limiting NKT cell function in vitro [67]. We found that both nAFP and tAFP led to significant downregulation of CD1d on DCs; however, this did not diminish their potential to stimulate NKT cells [67]. Additional work is needed to fully understand the interplay between DCs and NKT cells, including the modulation of cytokines produced by NKT cells, focusing on a role for lipids in this cellular immune interaction.…”

Alpha-fetoprotein Promotes the Malignant Phenotype of Hepatocellular Carcinoma Cells: the Drugs Resistance Origination

“…AFP can upregulate the expression of promoting apoptotic genes (such as Bax, Bid, Bad, etc. ), and induce apoptosis of immune cells (e.g., lymphocytes, dendritic cells) [93,94] . AFP can also upregulate the expression of proapoptotic factor genes in immuneinfiltrating cells in the tumor microenvironment.…”