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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 tumor cells promote partial DC maturation.Differentiating iMoDCs exposed to varying ratios of JU77 cells were stained for CD11c and maturation markers for flow cytometric analysis. CD11c+ DCs were identified as described in Fig 1. Expression of each surface marker was analyzed on gated CD11c+ cells; representative gating strategy is shown (A). Pooled data of the percent of iMoDCs expressing CD1a (B), CD86 (C), HLA-DR (E) and CD80 (G) and surface expression levels (shown as MFIs) of CD86 (D), HLA-DR (F) and CD80 (H) on iMoDCs is from 6 individuals and shown as mean ± SEM. * = p < 0.05; ** = p < 0.005.
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pone.0123563.g002: Mesothelioma tumor cells promote partial DC maturation.Differentiating iMoDCs exposed to varying ratios of JU77 cells were stained for CD11c and maturation markers for flow cytometric analysis. CD11c+ DCs were identified as described in Fig 1. Expression of each surface marker was analyzed on gated CD11c+ cells; representative gating strategy is shown (A). Pooled data of the percent of iMoDCs expressing CD1a (B), CD86 (C), HLA-DR (E) and CD80 (G) and surface expression levels (shown as MFIs) of CD86 (D), HLA-DR (F) and CD80 (H) on iMoDCs is from 6 individuals and shown as mean ± SEM. * = p < 0.05; ** = p < 0.005.

Mentions: Loss of the capacity to process antigen is associated with DC maturation. Thus, iMoDCs from the above experiment were assessed for expression of surface molecules associated with maturation; representative gating strategy is shown in Fig 2A. Expression of CD1a, a molecule involved in the presentation of lipid antigens to T cells, was examined. As the proportion of JU77 mesothelioma cells increased, the percentage of CD11c+ iMoDCs expressing CD1a decreased (Fig 2B). These data suggest impaired capacity to present lipid antigens to T cells in lipid-laden DCs however, reduced CD1a has also been associated with DC maturation [21].


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 tumor cells promote partial DC maturation.Differentiating iMoDCs exposed to varying ratios of JU77 cells were stained for CD11c and maturation markers for flow cytometric analysis. CD11c+ DCs were identified as described in Fig 1. Expression of each surface marker was analyzed on gated CD11c+ cells; representative gating strategy is shown (A). Pooled data of the percent of iMoDCs expressing CD1a (B), CD86 (C), HLA-DR (E) and CD80 (G) and surface expression levels (shown as MFIs) of CD86 (D), HLA-DR (F) and CD80 (H) on iMoDCs is from 6 individuals and shown as mean ± SEM. * = p < 0.05; ** = p < 0.005.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123563.g002: Mesothelioma tumor cells promote partial DC maturation.Differentiating iMoDCs exposed to varying ratios of JU77 cells were stained for CD11c and maturation markers for flow cytometric analysis. CD11c+ DCs were identified as described in Fig 1. Expression of each surface marker was analyzed on gated CD11c+ cells; representative gating strategy is shown (A). Pooled data of the percent of iMoDCs expressing CD1a (B), CD86 (C), HLA-DR (E) and CD80 (G) and surface expression levels (shown as MFIs) of CD86 (D), HLA-DR (F) and CD80 (H) on iMoDCs is from 6 individuals and shown as mean ± SEM. * = p < 0.05; ** = p < 0.005.
Mentions: Loss of the capacity to process antigen is associated with DC maturation. Thus, iMoDCs from the above experiment were assessed for expression of surface molecules associated with maturation; representative gating strategy is shown in Fig 2A. Expression of CD1a, a molecule involved in the presentation of lipid antigens to T cells, was examined. As the proportion of JU77 mesothelioma cells increased, the percentage of CD11c+ iMoDCs expressing CD1a decreased (Fig 2B). These data suggest impaired capacity to present lipid antigens to T cells in lipid-laden DCs however, reduced CD1a has also been associated with DC maturation [21].

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