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Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4⁺ Treg cells in ovarian cancer cells microenvironment.

ABSTRACT: Immunotherapy is expected to become the most promising new treatment for ovarian cancer owing to its immunogenicity. However, immunosuppression in the tumor microenvironment is a major obstacle to the efficacy of tumor therapy. Studies have found different metabolism ways of regulatory T cells (Tregs) in the cancer environment may be related to the immunosuppression and Toll-like receptor 8 (TLR8) can reverse the suppression function of Tregs. But it is still unclear that if the TLR8-mediated function reversal is associated with the change of glucose metabolism of Tregs. It was found that the positive expression rates of Glut1, HIF-1?, and Ki67 in CD4⁺ Treg cells of OC were significantly higher than that in benign ovarian tumor and HC, and also significantly higher than that in CD4⁺ Teffs of OC. What's more, compared with CD4⁺ Teff group, CD4⁺ Tregs highly expressed seven genes and three proteins related to glucose metabolism and had higher levels of glucose uptake and glycolysis. After activating TLR8 signal of CD4⁺ Tregs, the proliferation level of naive CD4⁺ T cells was higher than that of the control group. At the same time, the expression levels of eight genes and five proteins related to glucose metabolism in CD4⁺ Treg cells with TLR8 activated were decreased and levels of glucose uptake and glycolysis were also lower. Furthermore, TLR8 signaling also downregulated the mTOR pathway in CD4⁺ Tregs. CD4⁺ Tregs pretreated with 2-deoxy-d-Glucose (2-DG) and galloflavin also attenuated the inhibition of Teffs proliferation. Although CD4⁺ Tregs pretreated with 2-DG and galloflavin before activating TLR8 signal had no significant difference compared with the group only treated with inhibitors, which suggested TLR8-mediated reversal of CD4⁺ Treg cells inhibitory function in ovarian cancer cells co-cultured microenvironment had a causal relationship with glucose metabolism.

SUBMITTER: Xu R

PROVIDER: S-EPMC7790820 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4<sup>+</sup> Treg cells in ovarian cancer cells microenvironment.

Xu Rui R Wu Ming M Liu Shuna S Shang Wenwen W Li Rong R Xu Juan J Huang Lei L Wang Fang F

Cell death & disease 20210107 1

Immunotherapy is expected to become the most promising new treatment for ovarian cancer owing to its immunogenicity. However, immunosuppression in the tumor microenvironment is a major obstacle to the efficacy of tumor therapy. Studies have found different metabolism ways of regulatory T cells (Tregs) in the cancer environment may be related to the immunosuppression and Toll-like receptor 8 (TLR8) can reverse the suppression function of Tregs. But it is still unclear that if the TLR8-mediated fu ...[more]

PMID: 33414414

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Project description:BackgroundHuman endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are, respectively, encoded by adjacent X-linked genes. We previously established that TLR7 evades X chromosome inactivation (XCI) in female immune cells. Whether TLR8 also evades XCI, however, has not yet been explored.MethodIn the current study, we used RNA fluorescence in situ hybridization (RNA FISH) to directly visualize, on a single-cell basis, primary transcripts of TLR7 and TLR8 relative to X chromosome territories in CD14+ monocytes and CD4+ T lymphocytes from women, Klinefelter syndrome (KS) men, and euploid men. To assign X chromosome territories in cells lacking robust expression of a XIST compartment, we designed probes specific for X-linked genes that do not escape XCI and therefore robustly label the active X chromosome. We also assessed whether XCI escape of TLR8 was associated with sexual dimorphism in TLR8 protein expression by western blot and flow cytometry.ResultsUsing RNA FISH, we show that TLR8, like TLR7, evades XCI in immune cells, and that cells harboring simultaneously TLR7 and TLR8 transcript foci are more frequent in women and KS men than in euploid men, resulting in a sevenfold difference in frequency. This transcriptional bias was again observable when comparing the single X of XY males with the active X of cells from females or KS males. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in male cells.ConclusionsTLR8, mirroring TLR7, escapes XCI in human monocytes and CD4+ T cells. Co-dependent transcription from the active X chromosome and escape from XCI could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases.

Dataset Information

Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4⁺ Treg cells in ovarian cancer cells microenvironment.

Publications

Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4<sup>+</sup> Treg cells in ovarian cancer cells microenvironment.

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Dataset Information

Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4+ Treg cells in ovarian cancer cells microenvironment.

Publications

Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4<sup>+</sup> Treg cells in ovarian cancer cells microenvironment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4⁺ Treg cells in ovarian cancer cells microenvironment.