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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 cells promote production of tolerogenic cytokines by iMoDCs.Cytokine concentrations were measured in conditioned medium collected from co-cultures of immature MoDCs and JU77 tumor cells using a cytometric bead array; pooled data from 3 individuals is expressed as mean ± SEM (A). Cytokine concentrations were also measured in conditioned medium collected from cultured JU77 tumor cells; data is from one experiment (B). * = concentration below detection limit of assay.
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pone.0123563.g003: Mesothelioma cells promote production of tolerogenic cytokines by iMoDCs.Cytokine concentrations were measured in conditioned medium collected from co-cultures of immature MoDCs and JU77 tumor cells using a cytometric bead array; pooled data from 3 individuals is expressed as mean ± SEM (A). Cytokine concentrations were also measured in conditioned medium collected from cultured JU77 tumor cells; data is from one experiment (B). * = concentration below detection limit of assay.

Mentions: The effect of mesothelioma cells on iMoDC cytokine production was assessed using conditioned media collected from the above experiments. The pro-inflammatory cytokines TNF-α, IL-12p70 and IFN-γ were not detected in the culture media from DC and JU77 tumor cell co-cultures (Fig 3A). In contrast, the anti-inflammatory cytokine IL-10 was detected at all ratios of DCs:JU77 tumor cells (Fig 3A). JU77 cells alone did not produce IL-10 (Fig 3B), suggesting that the source of IL-10 was the iMoDCs. These data suggest that mesothelioma cells induce tolerogenic iMoDCs that disable anti-mesothelioma immune responses.


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 cells promote production of tolerogenic cytokines by iMoDCs.Cytokine concentrations were measured in conditioned medium collected from co-cultures of immature MoDCs and JU77 tumor cells using a cytometric bead array; pooled data from 3 individuals is expressed as mean ± SEM (A). Cytokine concentrations were also measured in conditioned medium collected from cultured JU77 tumor cells; data is from one experiment (B). * = concentration below detection limit of assay.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123563.g003: Mesothelioma cells promote production of tolerogenic cytokines by iMoDCs.Cytokine concentrations were measured in conditioned medium collected from co-cultures of immature MoDCs and JU77 tumor cells using a cytometric bead array; pooled data from 3 individuals is expressed as mean ± SEM (A). Cytokine concentrations were also measured in conditioned medium collected from cultured JU77 tumor cells; data is from one experiment (B). * = concentration below detection limit of assay.
Mentions: The effect of mesothelioma cells on iMoDC cytokine production was assessed using conditioned media collected from the above experiments. The pro-inflammatory cytokines TNF-α, IL-12p70 and IFN-γ were not detected in the culture media from DC and JU77 tumor cell co-cultures (Fig 3A). In contrast, the anti-inflammatory cytokine IL-10 was detected at all ratios of DCs:JU77 tumor cells (Fig 3A). JU77 cells alone did not produce IL-10 (Fig 3B), suggesting that the source of IL-10 was the iMoDCs. These data suggest that mesothelioma cells induce tolerogenic iMoDCs that disable anti-mesothelioma immune responses.

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