Induction of macrophage efferocytosis in pancreatic cancer via PI3Kγ inhibition and radiotherapy promotes tumour control

Gut, Journal Year: 2025, Volume and Issue: unknown, P. gutjnl - 333492

Published: Jan. 9, 2025

Background The immune suppression mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain unknown, but preclinical studies have implicated macrophage-mediated tolerance. Hence, pathways that regulate macrophage phenotype are of strategic interest, with reprogramming strategies focusing on inhibitors phosphoinositide 3-kinase-gamma (PI3Kγ) due to restricted cell expression. Inhibition PI3Kγ alone is ineffective PDAC, despite increased infiltration CD8+ T cells. Objective We hypothesised the stimulatory effects radiation, and its ability boost tumour antigen availability could synergise inhibition augment antitumour immunity. Design used orthoptic genetically engineered mouse models cancer (LSL-Kras G12D/+ ;Trp53 R172H/+ ;Pdx1-Cre). Stereotactic radiotherapy was delivered using contrast CT imaging, by oral administration. Changes microenvironment were quantified flow cytometry, multiplex immunohistochemistry RNA sequencing. Tumour-educated macrophages investigate efferocytosis, presentation activation. Single-cell sequencing data fresh samples autologous validate our findings. Results Tumour-associated employ efferocytosis eradicate apoptotic cells can be redirected present antigens, stimulate responses increase local control. Specifically, we demonstrate how signalling restricts inflammatory supports MERTK-dependent efferocytosis. further find combination targeted stimulates invoke a pathogen-induced like switches from tolerant presenting. Conclusions Our new immunotherapeutic approach translational rationale improve survival PDAC.

Language: Английский

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Combining bulk and scRNA‐seq to explore the molecular mechanisms governing the distinct efferocytosis activities of a macrophage subpopulation in PDAC

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(7)

Published: March 19, 2024

Abstract Pancreatic ductal adenocarcinoma (PDAC), a very aggressive tumour, is currently the third leading cause of cancer‐related deaths. Unfortunately, many patients face issue inoperability at diagnostic phase to quite dismal prognosis. The onset metastatic processes has crucial role in elevated mortality rates linked PDAC. Individuals with advances receive only palliative therapy and have grim It essential carefully analyse intricacies process enhance prognosis for individuals Malignancy development greatly impacted by macrophage efferocytosis. Our current knowledge about complete range efferocytosis activities PDAC their intricate interactions tumour cells still restricted. This work aims resolve communication gaps pinpoint transcription factor that vital immunological response populations. We analysed eight tissue samples sourced from gene expression omnibus. utilized several software packages such as Seurat, DoubletFinder, Harmony, Pi, GSVA, CellChat Monocle R together pySCENIC Python, single‐cell RNA sequencing (scRNA‐seq) data collected samples. study involved analysis comprehensive sample 22,124 cells, which were classified into distinct cell types. These types encompassed endothelial epithelial well various immune including CD4+ T CD8+ NK B plasma mast monocytes, DC different subtypes macrophages, namely C0 TGM2+, C1 PFN1+, C2 GAS6+ C3 APOC3+. differentiation between was achieved implementation CopyKat analysis, resulting detection categorization 1941 cells. amplification/deletion patterns observed on chromosomes differ significantly those Pseudotime Trajectories demonstrated subtype expressing TGM2+ had lowest level differentiation. Additionally, examination set scores related suggested this displayed higher activity during compared other subtypes. most active factors each identified BACH1, NFE2, TEAD4 ARID3A. In conclusion, human using immunofluorescence co‐localization CD68 CD11b within regions exhibiting presence keratin (KRT) alpha‐smooth muscle actin (α‐SMA). observation implies spatial association fibroblasts, There variation efferocytosis‐associated genes diversity might potentially influence advancement Moreover, central offers promising opportunity targeted immunotherapy treatment

Language: Английский

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The Multifaceted Roles of BACH1 in Disease: Implications for Biological Functions and Therapeutic Applications

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Abstract BTB domain and CNC homolog 1 (BACH1) belongs to the family of basic leucine zipper proteins is expressed in most mammalian tissues. It can regulate its own expression play a role transcriptionally activating or inhibiting downstream target genes. has crucial various biological processes, such as oxidative stress, cell cycle, heme homeostasis, immune regulation. Recent research highlights BACH1's significant regulatory roles series conditions, including stem pluripotency maintenance differentiation, growth, senescence, apoptosis. BACH1 closely associated with cardiovascular diseases contributes angiogenesis, atherosclerosis, restenosis, pathological cardiac hypertrophy, myocardial infarction, ischemia/reperfusion (I/R) injury. promotes tumor proliferation metastasis by altering metabolism epithelial‐mesenchymal transition phenotype. Moreover, appears show an adverse neurodegenerative diseases, gastrointestinal disorders, leukemia, pulmonary fibrosis, skin diseases. Inhibiting may be beneficial for treating these This review summarizes mechanism different types proposing that precise targeted intervention provide new strategies human disease prevention treatment.

Language: Английский

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Single-cell transcriptomic analysis reveals efferocytosis signature predicting immunotherapy response in hepatocellular carcinoma

Digestive and Liver Disease, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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