Mesothelioma tumor cells modulate dendritic cell lipid content, phenotype and function

Our plain-English summary of Mesothelioma tumor cells modulate dendritic cell lipid content, phenotype and function, by J.K. Gardner, C.D. Mamotte, P. Patel, et al (PloS One, 2015).

The study

• Authors: J.K. Gardner, C.D. Mamotte, P. Patel, T.L. Yeoh, C. Jackaman, D.J. Nelson
• Journal: PloS One
• Published: 2015;10(4):e0123563
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study examined whether mesothelioma cells alter the lipid (fat) content and behavior of dendritic cells, immune cells that help recognize tumors. The authors grew dendritic cells from 8 healthy volunteers' blood. They exposed these cells to human mesothelioma cells (JU77), to fluid from their cultures, and to blood lipoproteins. They also studied mice with tumors from a mouse mesothelioma line derived from an asbestos-injected mouse. Cells grown with tumor cells held significantly more lipid, processed a test antigen less well, showed more CD86, and released IL-10. A non-cancerous mesothelial line did not change antigen processing or CD86. Adding triglyceride-rich lipoproteins, but not LDL, to that fluid raised lipid levels more than the fluid alone. In mice, three dendritic cell types held more lipid in large than small tumors. In mice whose tumors carried the marker protein ovalbumin, transferred ovalbumin-specific CD8+ T cells multiplied less in nearby lymph nodes as tumors grew. The lipid-lowering drug TOFA did not lower dendritic cell lipid. The authors concluded that mesothelioma promotes dendritic cell lipid acquisition, associated with reduced ability to process and present antigens.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: cell culture (in vitro) experiments with human cells, plus animal experiments in mice (in vivo)
• Who was studied: Dendritic cells grown from the blood of 8 healthy volunteers (6 female, 2 male, aged 22 to 35). Cell lines: JU77, a human mesothelioma line from the pleural effusion of a patient; Met5A, a non-malignant human mesothelial line; AE17, a mouse mesothelioma line. Female C57BL/6J mice aged 6 to 8 weeks: in the main mouse experiments, 18 mice with small tumors, 9 with large tumors and 8 healthy controls. Work done at Curtin University, Perth, Australia.
• Exposure: Dendritic cells were exposed to mesothelioma tumor cells, to tumor cell-conditioned medium, and to triglyceride-rich lipoproteins or low-density lipoproteins (LDL). Mice were injected with AE17 or AE17sOVA mesothelioma cells. No asbestos exposure was studied directly; the AE17 line came from a mouse injected with asbestos fibres, and the fiber type is not named.
• Main results:
  • Immature human dendritic cells grown with JU77 mesothelioma cells had significantly higher lipid content than dendritic cells grown alone (data from 6 individuals).
  • Dendritic cells grown with tumor cells showed reduced antigen processing. Met5A (non-malignant mesothelial) cells did not alter antigen processing.
  • The percent of dendritic cells carrying CD86 rose significantly at all ratios of dendritic cells to JU77 cells. CD1a decreased as the proportion of tumor cells increased.
  • IL-10 was detected in dendritic cell and tumor cell co-cultures at all ratios. TNF-alpha, IL-12p70 and IFN-gamma were not detected (data from 3 individuals).
  • Tumor exposure did not interfere with the ability of immature dendritic cells to stimulate CD4+ or CD8+ T cell proliferation in a lab assay.
  • Dendritic cells exposed to tumor-conditioned medium (rather than tumor cells) had higher lipid levels, but their ability to take up and process antigen was retained and improved.
  • Adding triglyceride-rich lipoproteins, but not LDL, to JU77 tumor-conditioned medium raised dendritic cell lipid content more than conditioned medium alone (data from 4 individuals).
  • Mature dendritic cells exposed to tumor-conditioned medium did not show significant lipid changes. They produced less IL-12p70 (448 plus or minus 88.8 to 52.6 plus or minus 50.2 pg/ml) and less TNF-alpha (2,265 plus or minus 234.8 to 1,930 plus or minus 397.6 pg/ml), in cells from 2 healthy volunteers.
  • Mouse bone marrow-derived dendritic cells exposed to AE17 conditioned medium appeared to contain more lipid, but the difference was not statistically significant.
  • In mice, CD4+CD8alpha-, CD4-CD8alpha- and plasmacytoid dendritic cells inside tumors held more lipid in large tumors than in small tumors (18 mice with small, 9 with large tumors). CD8alpha+CD4- dendritic cells did not change in lipid but decreased in proportion. Dendritic cells in lymph nodes of tumor-bearing mice had lower lipid than in healthy mice.
  • In mice bearing AE17sOVA tumors, which express ovalbumin as a marker tumor antigen, proliferation of transferred ovalbumin-specific (OT-1) CD8+ T cells in draining lymph nodes was strong at days 7 and 14, began to diminish at day 21 and disappeared by day 28.
  • The lipid-lowering agent TOFA did not lower dendritic cell lipid content or restore dendritic cell function, in cell cultures or in mice.
• The authors' conclusion: The authors concluded that mesothelioma promotes lipid acquisition by dendritic cells. They wrote that this is associated with altered activation and reduced capacity to process and present antigens, which may impair anti-mesothelioma T cell responses.
• Limitations the authors state:
  • The authors did not identify the mechanism leading to dendritic cell dysfunction.
  • The impairment of lipid-laden dendritic cell subsets in mice was implied from lipid levels; the authors state that further functional studies are required.
  • The failure of TOFA may have been due to confounding effects of its diluent, DMSO.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Cytokine, Tumor Burden.

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