Distinct tumor-TAM interactions in IDH-stratified glioma microenvironments unveiled by single-cell and spatial transcriptomics.

Autor: Motevasseli M; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Darvishi M; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Khoshnevisan A; Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran., Zeinalizadeh M; Department of Neurosurgery, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran., Saffar H; Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran., Bayat S; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Najafi A; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Abbaspour MJ; Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran., Mamivand A; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Olson SB; Molecular and Medical Genetics, Knight Diagnostics Laboratories, Oregon Health and Science University, Portland, OR, USA., Tabrizi M; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. tabrizi@tums.ac.ir.; Molecular and Medical Genetics, Knight Diagnostics Laboratories, Oregon Health and Science University, Portland, OR, USA. tabrizi@tums.ac.ir.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2024 Aug 16; Vol. 12 (1), pp. 133. Date of Electronic Publication: 2024 Aug 16.
DOI: 10.1186/s40478-024-01837-5
Abstrakt: Tumor-associated macrophages (TAMs) residing in the tumor microenvironment (TME) are characterized by their pivotal roles in tumor progression, antitumor immunity, and TME remodeling. However, a thorough comparative characterization of tumor-TAM crosstalk across IDH-defined categories of glioma remains elusive, likely contributing to mixed outcomes in clinical trials. We delineated the phenotypic heterogeneity of TAMs across IDH-stratified gliomas. Notably, two TAM subsets with a mesenchymal phenotype were enriched in IDH-WT glioblastoma (GBM) and correlated with poorer patient survival and reduced response to anti-PD-1 immune checkpoint inhibitor (ICI). We proposed SLAMF9 receptor as a potential therapeutic target. Inference of gene regulatory networks identified PPARG, ELK1, and MXI1 as master transcription factors of mesenchymal BMD-TAMs. Our analyses of reciprocal tumor-TAM interactions revealed distinct crosstalk in IDH-WT tumors, including ANXA1-FPR1/3, FN1-ITGAVB1, VEGFA-NRP1, and TNFSF12-TNFRSF12A with known contribution to immunosuppression, tumor proliferation, invasion and TAM recruitment. Spatially resolved transcriptomics further elucidated the architectural organization of highlighted communications. Furthermore, we demonstrated significant upregulation of ANXA1, FN1, NRP1, and TNFRSF12A genes in IDH-WT tumors using bulk RNA-seq and RT-qPCR. Longitudinal expression analysis of candidate genes revealed no difference between primary and recurrent tumors indicating that the interactive network of malignant states with TAMs does not drastically change upon recurrence. Collectively, our study offers insights into the unique cellular composition and communication of TAMs in glioma TME, revealing novel vulnerabilities for therapeutic interventions in IDH-WT GBM.
(© 2024. The Author(s).)
Databáze: MEDLINE
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