Reprogramming the lipid metabolism of dendritic cells in tumor immunomodulation and immunotherapy

Sun, Zhanbo; Zhang, Lingyun; Liu, Lixian

doi:10.1016/j.biopha.2023.115574

Cited by 3 publications

(1 citation statement)

References 79 publications

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“…Additional immunosuppressive influences of accumulating fatty acids within the diverse tumor microenvironment have been described in myeloid populations that may have further implications for T cell responses. Within palmitate-enriched conditions, dendritic cells exhibit impaired antigen presentations, while tumor-associated macrophages undergo a metabolic switch toward fatty acid oxidation to support M2 polarization [53][54][55][56][57] . Thus, reducing fatty acid accumulation within the tumor microenvironment may help support improve anti-tumor immune responses.…”

Section: Discussionmentioning

confidence: 99%

Regulation of fatty acid delivery to metastases by tumor endothelium

Edwards,

Wang,

Song

et al. 2024

Preprint

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Tumor metastasis, the main cause of death in cancer patients, requires outgrowth of tumor cells after their dissemination and residence in microscopic niches. Nutrient sufficiency is a determinant of such outgrowth. Fatty acids (FA) can be metabolized by cancer cells for their energetic and anabolic needs but impair the cytotoxicity of T cells in the tumor microenvironment (TME), thereby supporting metastatic progression. However, despite the important role of FA in metastatic outgrowth, the regulation of intratumoral FA is poorly understood. In this report, we show that tumor endothelium actively promotes tumor growth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. This process uses transendothelial fatty acid transport via endosome cargo trafficking in a mechanism that requires mTORC1 activity. Thus, tumor burden was significantly reduced upon endothelial-specific targeted deletion of Raptor, a unique component of the mTORC1 complex (RptorECKO). In vivo trafficking of a fluorescent palmitic acid analog to tumor cells and T cells was reduced in RptorECKO lung metastatic tumors, which correlated with improved markers of T cell cytotoxicity. Combination of anti-PD1 with RAD001/everolimus, at a low dose that selectively inhibits mTORC1 in endothelial cells, impaired FA uptake in T cells and reduced metastatic disease, corresponding to improved anti-tumor immunity. These findings describe a novel mechanism of transendothelial fatty acid transfer into the TME during metastatic outgrowth and highlight a target for future development of therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Regulation of fatty acid delivery to metastases by tumor endothelium

Edwards,

Wang,

Song

et al. 2024

Preprint

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Metabolic regulation of the immune system in health and diseases: mechanisms and interventions

Hu,

Liu,

Lei

et al. 2024

Sig Transduct Target Ther

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Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases.

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Multifaceted bioinformatic analysis of m6A‐related ferroptosis and its link with gene signatures and tumour‐infiltrating immune cells in gliomas

Yang,

Hao,

Guiyang

et al. 2024

J Cellular Molecular Medi

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Whether N6‐Methyladenosine (m6A)‐ and ferroptosis‐related genes act on immune responses to regulate glioma progression remains unanswered. Data of glioma and corresponding normal brain tissues were fetched from the TCGA database and GTEx. Differentially expressed genes (DEGs) were identified for GO and KEGG enrichment analyses. The FerrDb database was based to yield ferroptosis‐related DEGs. Hub genes were then screened out using the cytoHubba database and validated in clinical samples. Immune cells infiltrating into the glioma tissues were analysed using the CIBERSORT R script. The association of gene signature underlying the m6A‐related ferroptosis with tumour‐infiltrating immune cells and immune checkpoints in low‐grade gliomas was analysed. Of 6298 DEGs enriched in mRNA modifications, 144 were ferroptosis‐related; NFE2L2 and METTL16 showed the strongest positive correlation. METTL16 knockdown inhibited the migrative and invasive abilities of glioma cells and induced ferroptosis in vitro. NFE2L2 was enriched in the anti‐m6A antibody. Moreover, METTL16 knockdown reduced the mRNA stability and level of NFE2L2 (both p < 0.05). Proportions of CD8+ T lymphocytes, activated mast cells and M2 macrophages differed between low‐grade gliomas and normal tissues. METTL16 expression was negatively correlated with CD8+ T lymphocytes, while that of NFE2L2 was positively correlated with M2 macrophages and immune checkpoints in low‐grade gliomas. Gene signatures involved in the m6A‐related ferroptosis in gliomas were identified via bioinformatic analyses. NFE2L2 interacted with METTL16 to regulate the immune response in low‐grade gliomas, and both molecules may be novel therapeutic targets for gliomas.

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Reprogramming the lipid metabolism of dendritic cells in tumor immunomodulation and immunotherapy

Cited by 3 publications

References 79 publications

Regulation of fatty acid delivery to metastases by tumor endothelium

Regulation of fatty acid delivery to metastases by tumor endothelium

Metabolic regulation of the immune system in health and diseases: mechanisms and interventions

Multifaceted bioinformatic analysis of m6A‐related ferroptosis and its link with gene signatures and tumour‐infiltrating immune cells in gliomas

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