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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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Mesothelioma-derived soluble factors modulate immature MoDC lipid content.Different concentrations of JU77 tumor cell-conditioned medium (TCM) were included in the human DC differentiation protocol (A) and lipid levels measured using BODIPY (shown as MFI; B). The antigen processing capacity of iMoDCs exposed to JU77 TCM was assessed using the DQ-OVA assay and is shown as DQ-OVA MFI (C). Expression of DC maturation markers was also measured. Pooled data shows the percent of iMoDCs positive for CD1a (D) and CD86 (E), and surface expression levels of CD86 on iMoDCs (shown as MFI; F) after exposure to varying concentrations of TCM. Pooled data in (B-F) is from 6 individuals. All data is shown as mean ± SEM. * = p < 0.05; ** = p < 0.005; *** = p < 0.0005.
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pone.0123563.g004: Mesothelioma-derived soluble factors modulate immature MoDC lipid content.Different concentrations of JU77 tumor cell-conditioned medium (TCM) were included in the human DC differentiation protocol (A) and lipid levels measured using BODIPY (shown as MFI; B). The antigen processing capacity of iMoDCs exposed to JU77 TCM was assessed using the DQ-OVA assay and is shown as DQ-OVA MFI (C). Expression of DC maturation markers was also measured. Pooled data shows the percent of iMoDCs positive for CD1a (D) and CD86 (E), and surface expression levels of CD86 on iMoDCs (shown as MFI; F) after exposure to varying concentrations of TCM. Pooled data in (B-F) is from 6 individuals. All data is shown as mean ± SEM. * = p < 0.05; ** = p < 0.005; *** = p < 0.0005.

Mentions: The modulation of MoDC differentiation by tumor cells could be mediated by cell-to-cell contact and/or factors secreted by tumor cells. Thus, the next series of studies investigated whether mesothelioma-derived factors could also modulate MoDC lipid content, function, phenotype and cytokine production. Human monocytes were cultured with varying concentrations of tumor cell-conditioned medium (TCM) collected from cultured JU77 cells (Fig 4A). Immature MoDCs exposed to JU77 TCM demonstrated significantly higher lipid levels relative to iMoDCs cultured without TCM (Fig 4B). These data suggest that tumor-derived factors present in JU77 TCM modulate iMoDC lipid accumulation.


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)

Mesothelioma-derived soluble factors modulate immature MoDC lipid content.Different concentrations of JU77 tumor cell-conditioned medium (TCM) were included in the human DC differentiation protocol (A) and lipid levels measured using BODIPY (shown as MFI; B). The antigen processing capacity of iMoDCs exposed to JU77 TCM was assessed using the DQ-OVA assay and is shown as DQ-OVA MFI (C). Expression of DC maturation markers was also measured. Pooled data shows the percent of iMoDCs positive for CD1a (D) and CD86 (E), and surface expression levels of CD86 on iMoDCs (shown as MFI; F) after exposure to varying concentrations of TCM. Pooled data in (B-F) is from 6 individuals. All data is shown as mean ± SEM. * = p < 0.05; ** = p < 0.005; *** = p < 0.0005.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123563.g004: Mesothelioma-derived soluble factors modulate immature MoDC lipid content.Different concentrations of JU77 tumor cell-conditioned medium (TCM) were included in the human DC differentiation protocol (A) and lipid levels measured using BODIPY (shown as MFI; B). The antigen processing capacity of iMoDCs exposed to JU77 TCM was assessed using the DQ-OVA assay and is shown as DQ-OVA MFI (C). Expression of DC maturation markers was also measured. Pooled data shows the percent of iMoDCs positive for CD1a (D) and CD86 (E), and surface expression levels of CD86 on iMoDCs (shown as MFI; F) after exposure to varying concentrations of TCM. Pooled data in (B-F) is from 6 individuals. All data is shown as mean ± SEM. * = p < 0.05; ** = p < 0.005; *** = p < 0.0005.
Mentions: The modulation of MoDC differentiation by tumor cells could be mediated by cell-to-cell contact and/or factors secreted by tumor cells. Thus, the next series of studies investigated whether mesothelioma-derived factors could also modulate MoDC lipid content, function, phenotype and cytokine production. Human monocytes were cultured with varying concentrations of tumor cell-conditioned medium (TCM) collected from cultured JU77 cells (Fig 4A). Immature MoDCs exposed to JU77 TCM demonstrated significantly higher lipid levels relative to iMoDCs cultured without TCM (Fig 4B). These data suggest that tumor-derived factors present in JU77 TCM modulate iMoDC lipid accumulation.

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