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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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Lipid levels of three DC subsets increase in large mesothelioma tumors.DC subsets were identified by first gating on CD11c+ DCs (A). Expression of CD4 versus CD8α was used to identify CD4+CD8α -, CD8α +CD4- and CD4-CD8α - DC subsets (B). Plasmacytoid DCs were identified as B220+Gr1+ cells (C). Lipid levels, shown as BODIPY MFI, were measured for CD8α +CD4- DCs (D), CD4+CD8α- DCs (E), CD4-CD8α- DCs (F) and plasmacytoid DCs (G) in small and large AE17 tumors: n = 18 mice with small tumors and n = 9 mice with large tumors. Pooled data are shown as mean ± SEM. ** = p < 0.005.
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pone.0123563.g008: Lipid levels of three DC subsets increase in large mesothelioma tumors.DC subsets were identified by first gating on CD11c+ DCs (A). Expression of CD4 versus CD8α was used to identify CD4+CD8α -, CD8α +CD4- and CD4-CD8α - DC subsets (B). Plasmacytoid DCs were identified as B220+Gr1+ cells (C). Lipid levels, shown as BODIPY MFI, were measured for CD8α +CD4- DCs (D), CD4+CD8α- DCs (E), CD4-CD8α- DCs (F) and plasmacytoid DCs (G) in small and large AE17 tumors: n = 18 mice with small tumors and n = 9 mice with large tumors. Pooled data are shown as mean ± SEM. ** = p < 0.005.

Mentions: Dendritic cells represent a heterogeneous population of cells comprised of several different subsets, each with different but related functions [22]. Four DC subsets were examined (Fig 8A–8C). CD8α+CD4- DCs play a key role in anti-tumor immunity due to their ability to cross-present tumor antigen to CD8+ T cells [23]. The CD8α- subsets, i.e. CD4+CD8 α- and CD4-CD8 α- are described as conventional DCs that induce T helper cell responses [23]. CD11c+B220+Gr1+ plasmacytoid DCs play a key role in innate/anti-viral immunity [24].


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)

Lipid levels of three DC subsets increase in large mesothelioma tumors.DC subsets were identified by first gating on CD11c+ DCs (A). Expression of CD4 versus CD8α was used to identify CD4+CD8α -, CD8α +CD4- and CD4-CD8α - DC subsets (B). Plasmacytoid DCs were identified as B220+Gr1+ cells (C). Lipid levels, shown as BODIPY MFI, were measured for CD8α +CD4- DCs (D), CD4+CD8α- DCs (E), CD4-CD8α- DCs (F) and plasmacytoid DCs (G) in small and large AE17 tumors: n = 18 mice with small tumors and n = 9 mice with large tumors. Pooled data are shown as mean ± SEM. ** = p < 0.005.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123563.g008: Lipid levels of three DC subsets increase in large mesothelioma tumors.DC subsets were identified by first gating on CD11c+ DCs (A). Expression of CD4 versus CD8α was used to identify CD4+CD8α -, CD8α +CD4- and CD4-CD8α - DC subsets (B). Plasmacytoid DCs were identified as B220+Gr1+ cells (C). Lipid levels, shown as BODIPY MFI, were measured for CD8α +CD4- DCs (D), CD4+CD8α- DCs (E), CD4-CD8α- DCs (F) and plasmacytoid DCs (G) in small and large AE17 tumors: n = 18 mice with small tumors and n = 9 mice with large tumors. Pooled data are shown as mean ± SEM. ** = p < 0.005.
Mentions: Dendritic cells represent a heterogeneous population of cells comprised of several different subsets, each with different but related functions [22]. Four DC subsets were examined (Fig 8A–8C). CD8α+CD4- DCs play a key role in anti-tumor immunity due to their ability to cross-present tumor antigen to CD8+ T cells [23]. The CD8α- subsets, i.e. CD4+CD8 α- and CD4-CD8 α- are described as conventional DCs that induce T helper cell responses [23]. CD11c+B220+Gr1+ plasmacytoid DCs play a key role in innate/anti-viral immunity [24].

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