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Lactate Reprograms Glioblastoma Immunity through CBX3-regulated Histone Lactylation [RNA-seq]

ABSTRACT: Lactate Reprograms Glioblastoma Immunity through CBX3-regulated Histone Lactylation [RNA-seq]

PROVIDER: PRJNA1030282 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26448712_1.fastq.gz	Fastqsanger.gz
	SRR26448712_2.fastq.gz	Fastqsanger.gz
	SRR26448713_1.fastq.gz	Fastqsanger.gz
	SRR26448713_2.fastq.gz	Fastqsanger.gz
	SRR26448714_1.fastq.gz	Fastqsanger.gz

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Lactate Reprograms Glioblastoma Immunity through CBX3-regulated Histone Lactylation

Project description:Lactate Reprograms Glioblastoma Immunity through CBX3-regulated Histone Lactylation

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Lactate Reprograms Glioblastoma Immunity through CBX3-regulated Histone Lactylation [RNA-seq]

Project description:Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades anti-tumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming towards glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of microglial phagocytosis via transcriptional upregulation of CD47, a “don’t eat me” signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) P300 to induce increased P300 substrate specificity toward lactyl-coA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates a metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immune-oncology therapies.

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Lactate Reprograms Glioblastoma Immunity through CBX3-regulated Histone Lactylation [ChIP-seq]

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Lactate Reprograms Glioblastoma Immunity through CBX3-regulated Histone Lactylation [ChIP-seq]

Project description:Lactate Reprograms Glioblastoma Immunity through CBX3-regulated Histone Lactylation [ChIP-seq]

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Tumor-associated macrophage derived lactate remodeling glioblastoma stem cells immune microenvironment through lactylation in glioblastoma

Project description:Glioblastoma (GBM) is a malignancy with the complex tumor microenvironment (TME) dominated by glioblastoma stem cells (GSCs) and infiltrated with tumor-associated macrophages (TAMs), exhibiting aberrant metabolism progress. Lactate is a critical glycolytic metabolite that promotes tumor progression. However, the mechanism of lactate transporting and lactylation in the tumor microenvironment (TME) of GBM remains elusive. Examination of lactate metabolic signature highly expressed on TAMs and tumor cells. We uncovered that TAMs provide lactate to GSCs, promoting GSCs proliferation and inducing the non-homologous end joining (NHEJ) protein KU70 lactylated at K317. Furthermore, TAM-derived lactate-inducing KU70 lactylation inhibits cGAS- type I interferon signaling, remodeling the immunosuppressive microenvironment through reduced cytotoxic CD8+ T cell infiltration, promoting the malignant progress of GBM. This study unveils TAMs-derived lactate and lactylation as a critical regulator of NHEJ, providing fresh insights into how aberrant lactylation and TME reprogramming are linked to DNA damage repair, which contributes to exploring new therapeutic strategies for targeting lactate transporters in combination with anti-PD-1-antibody to enhance anti-tumor immunity, which provides the theoretical basis for improving the clinical prognosis of GBM.

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Lactate Reprograms Glioblastoma Immunity through CBX3-regulated Histone Lactylation

Project description:This SuperSeries is composed of the SubSeries listed below.

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Tumor-associated macrophage derived lactate remodeling glioblastoma stem cells immune microenvironment through lactylation in glioblastoma

Project description:Tumor-associated macrophage derived lactate remodeling glioblastoma stem cells immune microenvironment through lactylation in glioblastoma

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Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma

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Hexokinase 2 and lactate mediated gene expression via histone H3 lysine 18 lactylation (CHO CUT&Tag)

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