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

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

PROVIDER: PRJNA1082724 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28197519_1.fastq.gz	Fastqsanger.gz
	SRR28197519_2.fastq.gz	Fastqsanger.gz
	SRR28197520_1.fastq.gz	Fastqsanger.gz
	SRR28197520_2.fastq.gz	Fastqsanger.gz
	SRR28197521_1.fastq.gz	Fastqsanger.gz

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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.

2024-05-06 | GSE260700 | GEO

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

2024-05-06 | GSE260701 | GEO

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

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

| PRJNA1082725 | ENA

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.

2023-10-26 | GSE245854 | GEO

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

2023-10-26 | GSE245853 | GEO

Inhibiting macrophage-derived lactate transport restores cGAS-STING signaling and enhances anti-tumour immunity in glioblastoma

Project description:Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by glioblastoma stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs), and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4/MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining (NHEJ) protein KU70 at lysine 317 (K317), which inhibits cGAS-STING signaling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for 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

| PRJNA1030272 | ENA

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

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

| PRJNA1030282 | ENA

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

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

| PRJNA1030279 | ENA

miRNA expression profiles of peripheral monocytes and glioblastoma-infiltrating macrophages

Project description:MicroRNAs (miRNAs) are non-coding molecules involved in post-transcriptional gene regulation that have been shown to modulate tumor cell proliferation and apoptosis and to act as oncogenes or tumor-suppressor genes. Although miRNAs have been linked to tumor progression, the connection between tumor-mediated immune modulation and miRNAs has yet to be explored. Specifically, how the miRNA dysregulation affects the monocyte-derived glioblastoma-infiltrating macrophages, the most abundant immune cell population within the glioblastoma microenvironment, and their immune suppressive properties has not been evaluated to date. Here we managed to purify the glioblastoma-infiltrating macrophages from the tumor microenvironment and compared their miRNA expression profile with the matched peripheral monocytes from the peripheral blood of the same GBM patient as well as with healthy donors. Of note, several most down-regulated miRNA candidates revealed in this study, including miR-142-3p, were also known for their role in mediating tumor-associated immunosuppression. These results suggest a novel approach to identify miRNA immune therapeutics using a two-step process: 1) screen miRNA expression from tumor-associated immune cells relative to normal immune cell, and 2) select and prioritize potential candidates on the basis of binding to immunosuppressive pathways or mechanisms. In the study presented here, 12 samples, including peripheral monocyte samples from 4 healthy donors, peripheral monocytes from 4 GBM patients and matched tumor-infiltrating macrophages extracted from the glioblastoma microenvironment, were used to acquire the miRNA expression profiles of 1732 unique mature miRNA sequences via the Phalanx Human miRNA OneArray Microarray v3 Platform.

2014-09-23 | E-GEOD-51332 | biostudies-arrayexpress

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