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

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

PROVIDER: PRJNA1108672 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28926637.fastq.gz	Fastqsanger.gz
	SRR28926638.fastq.gz	Fastqsanger.gz
	SRR28926639.fastq.gz	Fastqsanger.gz
	SRR28926640.fastq.gz	Fastqsanger.gz
	SRR28926641.fastq.gz	Fastqsanger.gz

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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.

2024-06-01 | GSE266884 | GEO

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]

2023-10-26 | GSE245853 | GEO

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

Project description:Macrophages are critical components of the immunosuppressive microenvironment that restrict anti-cancer immunity in glioblastoma (GBM). However, how GBM shapes the regulatory function of macrophages remains elusive. Here, we report that monocyte-derived macrophages (MDM), but not yolk-sac derived microglia (MG), exhibited potent immunosuppressive activity, which was mediated by a population of glycolytic GLUT1+MDM, in an IL10-dependent manner. GBM-derived factors reprogrammed MDM towards glycolytic cells with enhanced avidity for glucose, which was mostly used to generate lactate. In turn, intracellular lactate caused lactylation of histone lysine residues that promoted MDM immunosuppressive activity via regulation of Il10 expression. GBM-primed activation of PERK supported glucose metabolism and regulated GLUT1 expression through ATF4 in MDM. PERK-deletion in MDM abrogated histone lactylation and suppressive activity, thereby promoting polyfunctional T cell-infiltration of tumors. In combination with immunotherapy, PERK-deletion blocked GBM progression. Our study demonstrates that glucose-driven histone lactylation controls MDM immunosuppressive function; all in a PERK-dependent manner.

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

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Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).

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

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Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in brain tumors [RNA-seq]

2024-05-06 | GSE260701 | GEO