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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 factors may promote lipid accumulation in immature bone marrow-derived murine DCs.Murine bone marrow (BM) progenitor cells cultured with GM-CSF and IL-4 were exposed to TCM from the AE17 mesothelioma cell line (A). At day 10, immature BMDC lipid levels were measured by BODIPY staining (B). Immature BMDCs were matured for 2 days using LPS and were co-exposed to 50% AE17 TCM (C) before lipid levels were analyzed (D). Pooled data in (B) and (D) is from 2 experiments. All data is shown as mean ± SEM.
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pone.0123563.g006: Mesothelioma-derived factors may promote lipid accumulation in immature bone marrow-derived murine DCs.Murine bone marrow (BM) progenitor cells cultured with GM-CSF and IL-4 were exposed to TCM from the AE17 mesothelioma cell line (A). At day 10, immature BMDC lipid levels were measured by BODIPY staining (B). Immature BMDCs were matured for 2 days using LPS and were co-exposed to 50% AE17 TCM (C) before lipid levels were analyzed (D). Pooled data in (B) and (D) is from 2 experiments. All data is shown as mean ± SEM.

Mentions: Similar studies using murine bone marrow-derived DCs (BMDCs) were conducted to determine if factors derived from murine AE17 mesothelioma tumors could also influence DC lipid accumulation. Differentiating BMDCs exposed to AE17 TCM (Fig 6A) appeared to contain higher lipid levels than BMDCs cultured without TCM, but the differences did not reach statistical significance (Fig 6B). LPS-matured BMDCs exposed to AE17 TCM contained similar lipid levels relative to the controls (Fig 6C and 6D).


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 factors may promote lipid accumulation in immature bone marrow-derived murine DCs.Murine bone marrow (BM) progenitor cells cultured with GM-CSF and IL-4 were exposed to TCM from the AE17 mesothelioma cell line (A). At day 10, immature BMDC lipid levels were measured by BODIPY staining (B). Immature BMDCs were matured for 2 days using LPS and were co-exposed to 50% AE17 TCM (C) before lipid levels were analyzed (D). Pooled data in (B) and (D) is from 2 experiments. All data is shown as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123563.g006: Mesothelioma-derived factors may promote lipid accumulation in immature bone marrow-derived murine DCs.Murine bone marrow (BM) progenitor cells cultured with GM-CSF and IL-4 were exposed to TCM from the AE17 mesothelioma cell line (A). At day 10, immature BMDC lipid levels were measured by BODIPY staining (B). Immature BMDCs were matured for 2 days using LPS and were co-exposed to 50% AE17 TCM (C) before lipid levels were analyzed (D). Pooled data in (B) and (D) is from 2 experiments. All data is shown as mean ± SEM.
Mentions: Similar studies using murine bone marrow-derived DCs (BMDCs) were conducted to determine if factors derived from murine AE17 mesothelioma tumors could also influence DC lipid accumulation. Differentiating BMDCs exposed to AE17 TCM (Fig 6A) appeared to contain higher lipid levels than BMDCs cultured without TCM, but the differences did not reach statistical significance (Fig 6B). LPS-matured BMDCs exposed to AE17 TCM contained similar lipid levels relative to the controls (Fig 6C and 6D).

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