Ricerc@Sapienza

Dendritic cells (DCs) are the only antigen-presenting cells able to prime naïve T cells and
cross-prime antigen-specific CD8+ T cells. Their functionality is a requirement for the
induction and maintenance of long-lasting cancer immunity. Albeit intensively investigated,
the in vivo mechanisms underlying efficient antigen cross-processing and presentation
are not fully understood. Several pieces of evidence indicate that antigen transfer to DCs
mediated by microvesicles (MVs) enhances antigen immunogenicity. This mechanism
is also relevant for cross-presentation of those tumor-associated glycoproteins such as
MUC1 that are blocked in HLA class II compartment when internalized by DCs as soluble
molecules. Here, we present pieces of evidence that the internalization of tumor-derived
MVs modulates antigen-processing machinery of DCs. Employing MVs derived from
ovarian cancer ascites fluid and established tumor cell lines, we show that MV uptake
modifies DC phagosomal microenvironment, triggering reactive oxygen species (ROS)
accumulation and early alkalinization. Indeed, tumor MVs carry radical species and the
MV uptake by DCs counteracts the chemically mediated acidification of the phagosomal
compartment. Further pieces of evidence suggest that efficacious antigen cross-priming
of the MUC1 antigen carried by the tumor MVs results from the early signaling induced by
MV internalization and the function of the antigen-processing machinery of DCs. These
results strongly support the hypothesis that tumor-derived MVs impact antigen immunogenicity
by tuning the antigen-processing machinery of DCs, besides being carrier of
tumor antigens. Furthermore, these findings have important implications for the exploitation
of MVs as antigenic cell-free immunogen for DC-based therapeutic strategies.