INTERNATIONAL CONGRESS OF
CancerGenetics
RESEARCH Distinct tumor‑TAM interactions in IDH‑stratified glioma microenvironments unveiled by single‑cell and spatial transcriptomics
-
Meysam Motevasseli,1,*
1. Tehran University of Medical Sciences
- Introduction: Gliomas are the most aggressive form of brain tumors. Despite notable advancements in targeted and immunotherapies, the standard of care for glioblastoma (GB) has remained largely unchanged, predominantly due to the challenges posed by the intra-tumoral heterogeneity and its immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) residing in the TME are characterized by their pivotal roles in tumor progression, antitumor immunity and TME remodeling. However, knowledge of tumor-TAM crosstalk in major categories of gliomas remains elusive. In the current study, tumor-TAM crosstalk in IDH-WT and IDH-Mut gliomas was explored making use of single-cell and spatial transcriptomics to elucidate intricate mechanisms leading to aggressive phenotype of GB.
- Methods: Single cell RNA-seq (scRNA-seq) was used to dissect the heterogeneity of TME in IDH-stratified gliomas. Spatial distribution of annotated subpopulations was resolved by spatial transcriptomic data. Next, using SCISSOR R package, we integrated survival and genomic information provided by the TCGA reference with cell-type signatures of our scRNA-seq. pySCENIC was used to infer gene regulatory networks. Cell-cell communications was inferred to further investigate tumor-TAM interplay followed by expression analysis of key genes on human tumor tissues.
- Results: We delineated the phenotypic heterogeneity of TAMs across IDH-stratified gliomas. Notably, two TAM subsets with a mesenchymal phenotype were enriched in IDH-WT GB 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 GB.
- Conclusion: Our results suggest that aggressive properties of IDH-WT GB can be elucidated in part by the unique communications they form with their associated macrophages in TME.
- Keywords: Glioblastoma, tumor microenvironment, tumor-associated macrophage, immune checkpoint inhibitor
