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Mesothelioma tumor cells modulate dendritic cell lipid content, phenotype and function.

Gardner JK, Mamotte CD, Patel P, Yeoh TL, Jackaman C, Nelson DJ - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia; CHIRI Biosciences Research Precinct, Curtin University, Perth, Western Australia, Australia.

ABSTRACT
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.

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Triglyceride-rich lipoproteins and mesothelioma-derived soluble factors modulate immature MoDCs.During differentiation, immature MoDCs were exposed to 50% JU77 TCM, with the addition of either triglyceride-rich lipoproteins (TG) or low-density lipoproteins (LDL). The lipid content of MoDCs exposed to JU77 TCM +/- TG (A) or JU77 TCM +/- LDL (B) was measured using BODIPY MFI. The DQ-OVA assay was used to assess the antigen processing capacity of MoDCs exposed to JU77 TCM +/- TG (C) or JU77 TCM +/- LDL (D). Expression of CD1a and CD86 was also examined on MoDCs exposed to JU77 TCM +/- TG (E and G) or JU77 TCM +/- LDL (F and H). Data is from 4 individuals and is shown as mean ± SEM. * = p < 0.05.
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pone.0123563.g005: Triglyceride-rich lipoproteins and mesothelioma-derived soluble factors modulate immature MoDCs.During differentiation, immature MoDCs were exposed to 50% JU77 TCM, with the addition of either triglyceride-rich lipoproteins (TG) or low-density lipoproteins (LDL). The lipid content of MoDCs exposed to JU77 TCM +/- TG (A) or JU77 TCM +/- LDL (B) was measured using BODIPY MFI. The DQ-OVA assay was used to assess the antigen processing capacity of MoDCs exposed to JU77 TCM +/- TG (C) or JU77 TCM +/- LDL (D). Expression of CD1a and CD86 was also examined on MoDCs exposed to JU77 TCM +/- TG (E and G) or JU77 TCM +/- LDL (F and H). Data is from 4 individuals and is shown as mean ± SEM. * = p < 0.05.

Mentions: Since other studies have shown that triglyceride-laden DCs in cancer patients are functionally disabled [12], we then investigated the combined influence of mesothelioma-derived factors and lipoproteins on DC lipid accumulation. To do this, MoDCs were differentiated in the presence of JU77 TCM and TG-rich lipoproteins or low-density lipoproteins (LDL; a cholesterol-rich lipoprotein). Addition of TG-rich lipoproteins, but not LDL, to TCM resulted in a greater increase in iMoDC lipid content compared to TCM only (Fig 5A and 5B). Furthermore, iMoDCs exposed to TG-rich lipoproteins (either alone or in combination with TCM), but not LDL, had reduced antigen processing capacity (Fig 5C and 5D). Changes to iMoDC surface phenotype were also examined. Addition of TG-rich lipoproteins, but not LDL, to TCM resulted in a significant decrease in the percent of iMoDCs expressing CD1a relative to DCs exposed to TCM only (Fig 5E and 5F). However, addition of either lipoprotein to TCM did not affect the percent of cells expressing CD86, relative to TCM only (Fig 5G and 5H). These results suggest that TG-rich lipoproteins, but not LDL, promote further increases in tumor-driven DC lipid accumulation, which is associated with impaired DC antigen processing ability and reduced CD1a expression.


Mesothelioma tumor cells modulate dendritic cell lipid content, phenotype and function.

Gardner JK, Mamotte CD, Patel P, Yeoh TL, Jackaman C, Nelson DJ - PLoS ONE (2015)

Triglyceride-rich lipoproteins and mesothelioma-derived soluble factors modulate immature MoDCs.During differentiation, immature MoDCs were exposed to 50% JU77 TCM, with the addition of either triglyceride-rich lipoproteins (TG) or low-density lipoproteins (LDL). The lipid content of MoDCs exposed to JU77 TCM +/- TG (A) or JU77 TCM +/- LDL (B) was measured using BODIPY MFI. The DQ-OVA assay was used to assess the antigen processing capacity of MoDCs exposed to JU77 TCM +/- TG (C) or JU77 TCM +/- LDL (D). Expression of CD1a and CD86 was also examined on MoDCs exposed to JU77 TCM +/- TG (E and G) or JU77 TCM +/- LDL (F and H). Data is from 4 individuals and is shown as mean ± SEM. * = p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4401725&req=5

pone.0123563.g005: Triglyceride-rich lipoproteins and mesothelioma-derived soluble factors modulate immature MoDCs.During differentiation, immature MoDCs were exposed to 50% JU77 TCM, with the addition of either triglyceride-rich lipoproteins (TG) or low-density lipoproteins (LDL). The lipid content of MoDCs exposed to JU77 TCM +/- TG (A) or JU77 TCM +/- LDL (B) was measured using BODIPY MFI. The DQ-OVA assay was used to assess the antigen processing capacity of MoDCs exposed to JU77 TCM +/- TG (C) or JU77 TCM +/- LDL (D). Expression of CD1a and CD86 was also examined on MoDCs exposed to JU77 TCM +/- TG (E and G) or JU77 TCM +/- LDL (F and H). Data is from 4 individuals and is shown as mean ± SEM. * = p < 0.05.
Mentions: Since other studies have shown that triglyceride-laden DCs in cancer patients are functionally disabled [12], we then investigated the combined influence of mesothelioma-derived factors and lipoproteins on DC lipid accumulation. To do this, MoDCs were differentiated in the presence of JU77 TCM and TG-rich lipoproteins or low-density lipoproteins (LDL; a cholesterol-rich lipoprotein). Addition of TG-rich lipoproteins, but not LDL, to TCM resulted in a greater increase in iMoDC lipid content compared to TCM only (Fig 5A and 5B). Furthermore, iMoDCs exposed to TG-rich lipoproteins (either alone or in combination with TCM), but not LDL, had reduced antigen processing capacity (Fig 5C and 5D). Changes to iMoDC surface phenotype were also examined. Addition of TG-rich lipoproteins, but not LDL, to TCM resulted in a significant decrease in the percent of iMoDCs expressing CD1a relative to DCs exposed to TCM only (Fig 5E and 5F). However, addition of either lipoprotein to TCM did not affect the percent of cells expressing CD86, relative to TCM only (Fig 5G and 5H). These results suggest that TG-rich lipoproteins, but not LDL, promote further increases in tumor-driven DC lipid accumulation, which is associated with impaired DC antigen processing ability and reduced CD1a expression.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia; CHIRI Biosciences Research Precinct, Curtin University, Perth, Western Australia, Australia.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus