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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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CD8α+CD4- DC proportions decrease in mice with large mesothelioma tumors.DC subsets were identified as described in Fig 8. The proportions of CD8α+CD4- DCs (A), CD4+CD8α- DCs (B), CD4-CD8α- DCs (C) and plasmacytoid DCs (D) within small versus large AE17 tumors were compared. The proportion of CD8α+CD4- DCs in dLN (E) and spleens (F) of tumor-bearing mice were compared to healthy mice: n = 18 mice with small tumors, n = 9 mice with large tumors and n = 8 healthy control mice. Pooled data are shown as mean ± SEM. ** = p < 0.005.
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pone.0123563.g009: CD8α+CD4- DC proportions decrease in mice with large mesothelioma tumors.DC subsets were identified as described in Fig 8. The proportions of CD8α+CD4- DCs (A), CD4+CD8α- DCs (B), CD4-CD8α- DCs (C) and plasmacytoid DCs (D) within small versus large AE17 tumors were compared. The proportion of CD8α+CD4- DCs in dLN (E) and spleens (F) of tumor-bearing mice were compared to healthy mice: n = 18 mice with small tumors, n = 9 mice with large tumors and n = 8 healthy control mice. Pooled data are shown as mean ± SEM. ** = p < 0.005.

Mentions: The proportion of CD8α+CD4- DCs decreased significantly in large tumors compared to small tumors (Fig 9A). The proportion of other DC subsets in tumors did not change (Fig 9B–9D). Similar reductions in the percent of CD8α+CD4- DCs were seen in the dLN of large tumor-bearing mice (Fig 9E) and in the spleens of small and large tumor-bearing mice (Fig 9F). Other DC subsets in lymphoid organs of tumor-bearing mice did not change with tumor size (S8A–S8C Fig). These results suggest that increases in the lipid content of DC subsets occur mainly within the tumor. However, reductions in the proportions of CD8α+CD4- DCs extend beyond the tumor.


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)

CD8α+CD4- DC proportions decrease in mice with large mesothelioma tumors.DC subsets were identified as described in Fig 8. The proportions of CD8α+CD4- DCs (A), CD4+CD8α- DCs (B), CD4-CD8α- DCs (C) and plasmacytoid DCs (D) within small versus large AE17 tumors were compared. The proportion of CD8α+CD4- DCs in dLN (E) and spleens (F) of tumor-bearing mice were compared to healthy mice: n = 18 mice with small tumors, n = 9 mice with large tumors and n = 8 healthy control mice. Pooled data are shown as mean ± SEM. ** = p < 0.005.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123563.g009: CD8α+CD4- DC proportions decrease in mice with large mesothelioma tumors.DC subsets were identified as described in Fig 8. The proportions of CD8α+CD4- DCs (A), CD4+CD8α- DCs (B), CD4-CD8α- DCs (C) and plasmacytoid DCs (D) within small versus large AE17 tumors were compared. The proportion of CD8α+CD4- DCs in dLN (E) and spleens (F) of tumor-bearing mice were compared to healthy mice: n = 18 mice with small tumors, n = 9 mice with large tumors and n = 8 healthy control mice. Pooled data are shown as mean ± SEM. ** = p < 0.005.
Mentions: The proportion of CD8α+CD4- DCs decreased significantly in large tumors compared to small tumors (Fig 9A). The proportion of other DC subsets in tumors did not change (Fig 9B–9D). Similar reductions in the percent of CD8α+CD4- DCs were seen in the dLN of large tumor-bearing mice (Fig 9E) and in the spleens of small and large tumor-bearing mice (Fig 9F). Other DC subsets in lymphoid organs of tumor-bearing mice did not change with tumor size (S8A–S8C Fig). These results suggest that increases in the lipid content of DC subsets occur mainly within the tumor. However, reductions in the proportions of CD8α+CD4- DCs extend beyond the tumor.

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