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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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Tumor-DCs accumulate lipid and reduce numerically with disease progression.Mice were inoculated with 5 x 105 AE17 mesothelioma cells and tumors allowed to develop into small (< 40 mm2) or large (> 80 mm2) tumors. Total CD11c+ DCs within tumors and lymphoid organs were identified (A) and lipid levels measured using BODIPY staining shown as MFIs of CD11c+ DCs; representative samples shown (B). Pooled data show the proportions of CD11c+ DCs within tumors (C), spleens (D), dLN (E) and ndLN (F). Pooled data show the lipid content of CD11c+ DCs in AE17 tumors (G), spleens (H), dLN (I) and ndLN (J). Lymphoid organs from tumor-bearing mice were compared to those from healthy mice: n = 18 mice with small tumors, n = 9 mice with large tumors and n = 8 healthy control mice. All pooled data are shown as mean ± SEM.
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pone.0123563.g007: Tumor-DCs accumulate lipid and reduce numerically with disease progression.Mice were inoculated with 5 x 105 AE17 mesothelioma cells and tumors allowed to develop into small (< 40 mm2) or large (> 80 mm2) tumors. Total CD11c+ DCs within tumors and lymphoid organs were identified (A) and lipid levels measured using BODIPY staining shown as MFIs of CD11c+ DCs; representative samples shown (B). Pooled data show the proportions of CD11c+ DCs within tumors (C), spleens (D), dLN (E) and ndLN (F). Pooled data show the lipid content of CD11c+ DCs in AE17 tumors (G), spleens (H), dLN (I) and ndLN (J). Lymphoid organs from tumor-bearing mice were compared to those from healthy mice: n = 18 mice with small tumors, n = 9 mice with large tumors and n = 8 healthy control mice. All pooled data are shown as mean ± SEM.

Mentions: The next series of experiments investigated if similar results would be seen in vivo using the AE17 murine mesothelioma model. CD11c+ DC numbers and lipid levels were examined in mice bearing small (< 40 mm2) or large (> 80 mm2) mesothelioma tumors (Fig 7A and 7B). The proportion of tumor-infiltrating CD11c+ DCs decreased in large tumors compared to small tumors (Fig 7C). In contrast, CD11c+ DC proportions remained stable or were slightly elevated in the spleens, draining lymph nodes (dLN) and non-draining lymph nodes (ndLN) of tumor-bearing mice relative to healthy mice (Fig 7D–7F). CD11c+ DCs in large tumors appeared to contain higher lipid levels than DCs from small tumors (Fig 7G). The lipid content of CD11c+ DCs from spleens did not differ between tumor-bearing and healthy mice (Fig 7H). Unexpectedly, DCs in dLN and ndLN of tumor-bearing mice had lower lipid content than DCs in lymph nodes of healthy mice (Fig 7I and 7J). These data show that modulation of DC numbers and lipid content was restricted to the tumor microenvironment.


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)

Tumor-DCs accumulate lipid and reduce numerically with disease progression.Mice were inoculated with 5 x 105 AE17 mesothelioma cells and tumors allowed to develop into small (< 40 mm2) or large (> 80 mm2) tumors. Total CD11c+ DCs within tumors and lymphoid organs were identified (A) and lipid levels measured using BODIPY staining shown as MFIs of CD11c+ DCs; representative samples shown (B). Pooled data show the proportions of CD11c+ DCs within tumors (C), spleens (D), dLN (E) and ndLN (F). Pooled data show the lipid content of CD11c+ DCs in AE17 tumors (G), spleens (H), dLN (I) and ndLN (J). Lymphoid organs from tumor-bearing mice were compared to those from healthy mice: n = 18 mice with small tumors, n = 9 mice with large tumors and n = 8 healthy control mice. All pooled data are 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.g007: Tumor-DCs accumulate lipid and reduce numerically with disease progression.Mice were inoculated with 5 x 105 AE17 mesothelioma cells and tumors allowed to develop into small (< 40 mm2) or large (> 80 mm2) tumors. Total CD11c+ DCs within tumors and lymphoid organs were identified (A) and lipid levels measured using BODIPY staining shown as MFIs of CD11c+ DCs; representative samples shown (B). Pooled data show the proportions of CD11c+ DCs within tumors (C), spleens (D), dLN (E) and ndLN (F). Pooled data show the lipid content of CD11c+ DCs in AE17 tumors (G), spleens (H), dLN (I) and ndLN (J). Lymphoid organs from tumor-bearing mice were compared to those from healthy mice: n = 18 mice with small tumors, n = 9 mice with large tumors and n = 8 healthy control mice. All pooled data are shown as mean ± SEM.
Mentions: The next series of experiments investigated if similar results would be seen in vivo using the AE17 murine mesothelioma model. CD11c+ DC numbers and lipid levels were examined in mice bearing small (< 40 mm2) or large (> 80 mm2) mesothelioma tumors (Fig 7A and 7B). The proportion of tumor-infiltrating CD11c+ DCs decreased in large tumors compared to small tumors (Fig 7C). In contrast, CD11c+ DC proportions remained stable or were slightly elevated in the spleens, draining lymph nodes (dLN) and non-draining lymph nodes (ndLN) of tumor-bearing mice relative to healthy mice (Fig 7D–7F). CD11c+ DCs in large tumors appeared to contain higher lipid levels than DCs from small tumors (Fig 7G). The lipid content of CD11c+ DCs from spleens did not differ between tumor-bearing and healthy mice (Fig 7H). Unexpectedly, DCs in dLN and ndLN of tumor-bearing mice had lower lipid content than DCs in lymph nodes of healthy mice (Fig 7I and 7J). These data show that modulation of DC numbers and lipid content was restricted to the tumor microenvironment.

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