Mesothelioma Tumor Cells Modulate Dendritic Cell Lipid Content, Phenotype and Function

Gardner, Joanne K.; Mamotte, Cyril; Patel, Priya; Yeoh, Teong Ling; Jackaman, Connie; Nelson, Delia J.

doi:10.1371/journal.pone.0123563

Cited by 37 publications

(23 citation statements)

References 46 publications

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“…These DCs exhibited endoplasmic reticulum (ER) stress and robust activation of an ER stress response factor spliced X-box-binding protein 1, which induced triglyceride biosynthesis leading to abnormal lipid accumulation. Other recent studies confirmed that dysfunction of DCs in radiation-induced thymic lymphoma and mesothelioma was mainly due to lipid accumulation [78, 79] (Fig. 2).…”

Section: Dysfunction In Cancersupporting

confidence: 64%

Dendritic cells in cancer: the role revisited

Veglia

Gabrilovich

2017

Current Opinion in Immunology

370

290

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Dendritic cells (DCs) with their potent antigen presenting ability are long considered as critical factor in antitumor immunity. Despite high potential in promoting antitumor responses, tumor-associated DCs are largely defective in their functional activity and can contribute to immune suppression in cancer. In recent years existence of immune suppressive regulatory DCs in tumor microenvironment was described. Monocytic myeloid derived suppressor cells (M-MDSCs) can contribute to the pool of tumor associated DCs by differentiating to inflammatory DCs (inf-DCs), which appear to have specific phenotype and is critical component of antitumor response. Here we examine the role of inf-DCs along with other DC subsets in the regulation of immune responses in cancer. These novel data expand our view on the role of DCs in cancer and may provide new targets for immunotherapy.

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Section: Dysfunction In Cancersupporting

confidence: 64%

Dendritic cells in cancer: the role revisited

Veglia

Gabrilovich

2017

Current Opinion in Immunology

370

290

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“…Recently, several studies have addressed the important role of lipids in immune cells, including dendritic cells and myeloid‐derived suppressor cells (MDSC) 16,17,26,27 . It has been shown that lipid accumulation driven by tumor‐derived factors contributes to tumor‐associated DC dysfunction in several cancers 16,27,28 . Similarly, MDSC took up the high lipid content, leading to profound metabolic and functional changes 17 .…”

Section: Discussionmentioning

confidence: 99%

Lipid accumulation in macrophages confers protumorigenic polarization and immunity in gastric cancer

et al. 2020

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Heterotypic interactions between tumor cells and macrophages can enable tumor progression and hold potential for the development of therapeutic interventions. However, the communication between tumors and macrophages and its mechanism are poorly understood. Here, we find that tumor‐associated macrophages (TAM) from tumor‐bearing mice have high amounts of lipid as compared to macrophages from tumor‐free mice. TAM also present high lipid content in clinical human gastric cancer patients. Functionally, TAM with high lipid levels are characterized by polarized M2‐like profiling, and exhibit decreased phagocytic potency and upregulated programmed death ligand 1 (PD‐L1) expression, blocking anti–tumor T cell responses to support their immunosuppressive function. Mechanistically, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identifies the specific PI3K pathway enriched within lipid‐laid TAM. Lipid accumulation in TAM is mainly caused by increased uptake of extracellular lipids from tumor cells, which leads to the upregulated expression of gamma isoform of phosphoinositide 3‐kinase (PI3K‐γ) polarizing TAM to M2‐like profiling. Correspondingly, a preclinical gastric cancer model is used to show pharmacological targeting of PI3K‐γ in high‐lipid TAM with a selective inhibitor, IPI549. IPI549 restores the functional activity of macrophages and substantially enhances the phagocytosis activity and promotes cytotoxic‐T‐cell‐mediated tumor regression. Collectively, this symbiotic tumor‐macrophage interplay provides a potential therapeutic target for gastric cancer patients through targeting PI3K‐γ in lipid‐laden TAM.

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“…The AE17 mesothelioma cell line was generated by the injection of asbestos fibers intraperitoneally into C57BL/6 mice. To generate the AE17sOVA tumor cell line, AE17 tumor cells were transfected with full-length secretory ovalbumin (OVA) (14,15). AE17sOVA cells can generate in vivo OVA-specific T cell responses (14) and this model is therefore suitable for in vivo tracking of both endogenous and adoptively-transferred antigen-specific CD8 + T cells.…”

Section: Ova-specific Ctl Become Progressively Exhausted In the Ae17smentioning

confidence: 99%

“…Despite these major advances and breakthroughs however, there remains a great need to better understand the mechanisms by which the immune system and CTL fail in the context of solid tumors (13), as not all patients respond to the current antibody blockade therapies (6,9,11). We therefore sought to characterize the development of T cell exhaustion in a murine mesothelioma model expressing ovalbumin, AE17sOVA, which exhibits histological and morphological similarities to human mesothelioma tumors (14,15). In this model, we observed that naïve OT-I CD8 + T cells, transgenic CD8 + T cells that recognize the SIINFEKL peptide from OVA, adoptively transferred concurrently with tumor cells differentiate into effector CTL by day 15 and developed characteristics of T cell exhaustion by the late end-point day 22.…”

Section: Introductionmentioning

confidence: 99%

Microenvironment-Dependent Gradient of CTL Exhaustion in the AE17sOVA Murine Mesothelioma Tumor Model

et al. 2020

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The immune system, and in particular, cytotoxic CD8 + T cells (CTLs), plays a vital part in the prevention and elimination of tumors. In many patients, however, CTL-mediated tumor killing ultimately fails in the clearance of cancer cells resulting in disease progression, in large part due to the progression of effector CTL into exhausted CTL. While there have been major breakthroughs in the development of CTL-mediated "reinvigoration"-driven immunotherapies such as checkpoint blockade therapy, there remains a need to better understand the drivers behind the development of T cell exhaustion. Our study highlights the unique differences in T cell exhaustion development in tumor-specific CTL which arises over time in a mouse model of mesothelioma. Importantly, we also show that peripheral tumor-specific T cells have a unique expression profile compared to exhausted tumor-infiltrating CTL at a late-stage of tumor progression in mice. Together, these data suggest that greater emphasis should be placed on understanding contributions of individual microenvironments in the development of T cell exhaustion.

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Mesothelioma Tumor Cells Modulate Dendritic Cell Lipid Content, Phenotype and Function

Cited by 37 publications

References 46 publications

Dendritic cells in cancer: the role revisited

Dendritic cells in cancer: the role revisited

Lipid accumulation in macrophages confers protumorigenic polarization and immunity in gastric cancer

Microenvironment-Dependent Gradient of CTL Exhaustion in the AE17sOVA Murine Mesothelioma Tumor Model

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