Tumor-derived alpha-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells (TUM4P.929)

Abstract

Abstract Alpha-fetoprotein (AFP) is a well-established serum biomarker used in the diagnosis of several epithelial cancers and abnormalities of prenatal development. It has been proposed that AFP, an oncofetal antigen that is re-expressed particularly in hepatocellular carcinomas (HCC), plays an immunoregulatory role. In this study, human peripheral blood monocytes were cultured in the presence of cord blood-derived normal AFP (nAFP) or HCC tumor-derived AFP (tAFP). We unexpectedly observed that low doses of tAFP, but not nAFP, interferes with DC differentiation. These tAFP-conditioned DC expressed diminished levels of DC maturation markers, retained a monocyte-like morphology, and exhibited limited production of inflammatory mediators. Moreover, the ability of tAFP-conditioned DC to induce a robust T cell proliferative response to both alloantigen and cognate antigen was markedly compromised. Further analysis revealed that low molecular weight species that co-purify with AFP must be present in order for tAFP-mediated DC dysfunction to occur. Notably, in HCC patients exhibiting high levels of serum AFP, we have observed a lower ratio of myeloid-to-plasmacytoid circulating DC in comparison to AFPlow patients, suggesting that elevated levels of tAFP in cancer patients impair DC differentiation and function on multiple levels. Therefore, novel therapeutic approaches that antagonize tAFP regulatory circuits will be critical to improve clinical outcomes.