Targeting mesenchymal monocyte-derived macrophages to enhance the sensitivity of glioblastoma to temozolomide by inhibiting TNF/CELSR2/p65/Kla-HDAC1/EPAS1 axis.

in Journal of advanced research by Wei Gao, Xinmiao Long, Xiang Lin, Kun Deng, Danyang Li, Meng Huang, Xiangyu Wang, Qing Liu, Minghua Wu

TLDR

  • The study identified a novel subtype of MDM that promotes GBM progression and TMZ resistance, and targeting this subtype with TREM1 inhibitory peptides enhanced the effectiveness of TMZ and anti-PD-1 immunotherapy.
  • Key Insights: The study highlights the importance of the tumor microenvironment in GBM development and provides a potential therapeutic strategy for treating MES-subtype GBM.

Abstract

Temozolomide (TMZ) resistance poses a significant challenge to the treatment of aggressive and highly lethal glioblastomas (GBM). Monocyte-derived Macrophages (MDM) within the tumor microenvironment are key factors contributing to TMZ resistance in GBM. Lactate-mediated histone lysine lactylation (Kla) plays a crucial role in the regulation of tumor progression. However, the mechanism through which MDM-induced Kla expression promotes TMZ resistance in GBM remains unclear. The objective of this study s to identify a subtype of MDM with therapeutic potential target and to elucidate the mechanisms through which this subtype of MDM contributes to tumor malignant progression and TMZ resistance. We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics data to evaluate whether mesenchymal (MES) MDM is associated with poor prognosis. By establishing a subtype model of GBM cells for the first time, we validated the mechanism by which MES-MDM promotes subtype conversion of tumor cells. Using patient-derived GBM organoids and an intracranial orthotopic GBM model, we demonstrated that targeting MES-MDMs increased GBM sensitivity to TMZ treatment. We identified a novel MDM subtype, MES-MDM, in the hypoxic niches of the perinecrotic region characterized by high TREM1 expression, which fueled GBM progression. Hypoxia drived MES-MDM signatures by activating ATF3 transcription. MES-MDM facilitated the transition from the NPC to the MES subtype in GBM cells, in which Histone Deacetylase 1 (HDAC1) Kla, induced by the TNF-CELSR2/p65 signaling pathway, promoted this conversion, thereby promoting TMZ resistance. Targeting MES-MDM with TREM1 inhibitory peptides amplified TMZ sensitivity, offering a potential strategy for overcoming resistance to therapy in GBM. Targeting TREM1 enhanced the effectiveness of anti-PD-1 immunotherapy. This study provides a potential therapeutic strategy for patients with MES-subtype GBM by targeting MES-MDMs in combination with TMZ or PD-1 antibody treatment.

Overview

  • The study aimed to identify a subtype of Monocyte-derived Macrophages (MDM) with therapeutic potential and elucidate its mechanisms in promoting glioblastoma (GBM) malignant progression and Temozolomide (TMZ) resistance.
  • The researchers integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics data to identify mesenchymal (MES) MDM as a subtype associated with poor prognosis.
  • The primary objective was to validate the mechanism by which MES-MDM promotes subtype conversion of tumor cells and investigate its therapeutic potential.

Comparative Analysis & Findings

  • The study identified a novel MDM subtype, MES-MDM, characterized by high TREM1 expression in the hypoxic niches of the perinecrotic region, which fueled GBM progression.
  • MES-MDM facilitated the transition from the NPC to the MES subtype in GBM cells, which was promoted by Histone Deacetylase 1 (HDAC1) Kla induced by the TNF-CELSR2/p65 signaling pathway.
  • Targeting MES-MDM with TREM1 inhibitory peptides amplified TMZ sensitivity and enhanced the effectiveness of anti-PD-1 immunotherapy.

Implications and Future Directions

  • The study provides a potential therapeutic strategy for patients with MES-subtype GBM by targeting MES-MDMs in combination with TMZ or PD-1 antibody treatment.
  • Future studies should investigate the underlying mechanisms of MES-MDM-induced subtype conversion and its implications for GBM progression and TMZ resistance.
  • The findings also highlight the importance of considering the tumor microenvironment, including MDMs, in the development of novel therapeutic strategies for GBM.
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