Dataset Information

Myeloid-Specific Acly Deletion Alters Macrophage Phenotype In Vitro and In Vivo without Affecting Tumor Growth.

ABSTRACT: Cancer cells rely on ATP-citrate lyase (Acly)-derived acetyl-CoA for lipid biogenesis and proliferation, marking Acly as a promising therapeutic target. However, inhibitors may have side effects on tumor-associated macrophages (TAMs). TAMs are innate immune cells abundant in the tumor microenvironment (TME) and play central roles in tumorigenesis, progression and therapy response. Since macrophage Acly deletion was previously shown to elicit macrophages with increased pro- and decreased anti-inflammatory responses in vitro, we hypothesized that Acly targeting may elicit anti-tumor responses in macrophages, whilst inhibiting cancer cell proliferation. Here, we used a myeloid-specific knockout model to validate that absence of Acly decreases IL-4-induced macrophage activation. Using two distinct tumor models, we demonstrate that Acly deletion slightly alters tumor immune composition and TAM phenotype in a tumor type-dependent manner without affecting tumor growth. Together, our results indicate that targeting Acly in macrophages does not have detrimental effects on myeloid cells.

SUBMITTER: de Goede KE

PROVIDER: S-EPMC8235155 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Myeloid-Specific Acly Deletion Alters Macrophage Phenotype <i>In Vitro</i> and <i>In Vivo</i> without Affecting Tumor Growth.

de Goede Kyra E KE Verberk Sanne G S SGS Baardman Jeroen J Harber Karl J KJ van Kooyk Yvette Y de Winther Menno P J MPJ Schetters Sjoerd T T STT Van den Bossche Jan J

Cancers 20210619 12

Cancer cells rely on ATP-citrate lyase (Acly)-derived acetyl-CoA for lipid biogenesis and proliferation, marking Acly as a promising therapeutic target. However, inhibitors may have side effects on tumor-associated macrophages (TAMs). TAMs are innate immune cells abundant in the tumor microenvironment (TME) and play central roles in tumorigenesis, progression and therapy response. Since macrophage Acly deletion was previously shown to elicit macrophages with increased pro- and decreased anti-inf ...[more]

PMID: 34205266

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Project description:BackgroundCellular interactions between thymocytes and thymic stromal cells are critical for normal T cell development. Thymic epithelial cells (TECs) are important stromal niche cells that provide essential growth factors, cytokines, and present self-antigens to developing thymocytes. The identification of genes that mediate cellular crosstalk in the thymus is ongoing. One candidate gene, Adam17, encodes a metalloprotease that functions by cleaving the ectodomain of several transmembrane proteins and regulates various developmental processes. In conventional Adam17 knockout mice, a non-cell autonomous role for ADAM17 in adult T cell development was reported, which strongly suggested that expression of ADAM17 in TECs was required for normal T cell development. However, knockdown of Adam17 results in multisystem developmental defects and perinatal lethality, which has made study of the role of Adam17 in specific cell types difficult. Here, we examined T cell and thymic epithelial cell development using a conditional knockout approach.Methodology/principal findingsWe generated an Adam17 conditional knockout mouse in which floxed Adam17 is deleted specifically in TECs by Cre recombinase under the control of the Foxn1 promoter. Normal T cell lineage choice and development through the canonical αβ T cell stages was observed. Interestingly, Adam17 deficiency in TECs resulted in reduced expression of the transcription factor Aire. However, no alterations in the patterns of TEC phenotypic marker expression and thymus morphology were noted.Conclusions/significanceIn contrast to expectation, our data clearly shows that absence of Adam17 in TECs is dispensable for normal T cell development. Differentiation of TECs is also unaffected by loss of Adam17 based on phenotypic markers. Surprisingly, we have uncovered a novel genetic link between Adam17and Aire expression in vivo. The cell type in which ADAM17 mediates its non-cell autonomous impact and the mechanisms by which it regulates intrathymic T cell development remain to be identified.

Dataset Information

Myeloid-Specific Acly Deletion Alters Macrophage Phenotype In Vitro and In Vivo without Affecting Tumor Growth.

Publications

Myeloid-Specific Acly Deletion Alters Macrophage Phenotype <i>In Vitro</i> and <i>In Vivo</i> without Affecting Tumor Growth.

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