Dendritic cells (DCs) play an important role in the generation of anti-
cancer immune responses, however there is evidence that DCs in
cancer patients are dysfunctional.
Lipid accumulation driven by
tumor-derived factors has recently been shown to contribute to DC dysfunction in several human
cancers, but has not yet been examined in
mesothelioma. This study investigated if
mesothelioma tumor cells and/or their secreted factors promote increases in DC
lipid content and modulate DC function. Human monocyte-derived DCs (MoDCs) were exposed to human
mesothelioma tumor cells and
tumor-derived factors in the presence or absence of
lipoproteins. The data showed that immature MoDCs exposed to
mesothelioma cells or factors contained increased
lipid levels relative to control DCs.
Lipid accumulation was associated with reduced antigen processing ability (measured using a DQ OVA assay), upregulation of the co-stimulatory molecule, CD86, and production of the tolerogenic
cytokine,
IL-10. Increases in DC
lipid content were further enhanced by co-exposure to
mesothelioma-derived factors and
triglyceride-rich
lipoproteins, but not
low-density lipoproteins. In vivo studies using a murine
mesothelioma model showed that the
lipid content of
tumor-infiltrating CD4+ CD8α- DCs, CD4- CD8α- DCs DCs and plasmacytoid DCs increased with
tumor progression. Moreover, increasing
tumor burden was associated with reduced proliferation of
tumor-antigen-specific CD8+ T cells in
tumor-draining lymph nodes. This study shows that
mesothelioma promotes DC
lipid acquisition, which is associated with altered activation status and reduced capacity to process and present
antigens, which may impair the ability of DCs to generate effective anti
mesothelioma T cell responses.