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Integrated immune profiling of chordomas reveals spatially organized niches and functional heterogeneity

Arrieta VA, Benotmane JK, Du R, Habashy KJ, Zhao J, Najem H, Wang S, Hou D, Katz JL, Vázquez-Cervantes GI, Castro B, Cholak ME, Pandey S, Tan SK, Parker M, Han Y, Kostelecky N, Vormittag-Nocito E, Santana-Santos L, Jennings L, Jamshidi P, Horbinski CM, Miska JM, Sonabend AM, Stupp R, Bettegowda C, Heimberger AB, Lesniak MS, Chandler JP, Wolinsky JP, Heiland DH, Lee Chang C (2026)

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Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 28

Pages Range: 440-453

Journal Issue: 2

DOI: 10.1093/neuonc/noaf213

Abstract

Background Chordomas are locally aggressive notochordal tumors with no systemic therapy options. As an ultra-rare cancer type, our understanding of its immune landscape is limited. While tumor-associated macrophages (TAMs) and T cells are critical components of the immune landscape, their functional states and interactions remain poorly understood. Methods We conducted an integrative analysis of 35 chordoma samples and six paired tumor-PBMC samples using single-cell RNA sequencing (scRNA-seq), T-cell receptor (TCR) profiling, and multiplex immunofluorescence. Immune cell phenotypes, spatial distribution, TCR motif diversity, and functional states were assessed using unbiased co-expression network analysis and predictive modeling. Results Chordomas exhibited remarkable immune cell heterogeneity, ranging from highly infiltrated to immune-­desert tumors. Tumor-associated macrophages dominated the tumor microenvironment (TME) and were enriched for antigen-processing pathways. T-cell receptor profiling revealed clonal overlap between tumor-infiltrating and peripheral T cells, suggesting systemic anti-tumor responses. Exhausted CD8+ T cells exhibited restricted clonality and tumor-specific amino acid motifs. Weighted gene co-expression network analysis (WGCNA) identified gene modules associated with immune activation and suppression, underscoring the dual roles of immune cells in the TME. Spatial analysis revealed fibrous septa as immune interaction hubs, where immune cell clustering was significantly higher than in tumor regions. Conclusions This study advances understanding of the chordoma immune landscape by integrating spatial, transcriptomic, and TCR data. The findings highlight systemic and local immune dynamics, reveal tumor-specific TCR motifs, and identify potential therapeutic targets. These insights provide a foundation for developing personalized immunotherapies to overcome immune suppression and enhance anti-tumor immunity in chordomas.

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How to cite

APA:

Arrieta, V.A., Benotmane, J.K., Du, R., Habashy, K.J., Zhao, J., Najem, H.,... Lee Chang, C. (2026). Integrated immune profiling of chordomas reveals spatially organized niches and functional heterogeneity. Neuro-Oncology, 28(2), 440-453. https://doi.org/10.1093/neuonc/noaf213

MLA:

Arrieta, Victor A., et al. "Integrated immune profiling of chordomas reveals spatially organized niches and functional heterogeneity." Neuro-Oncology 28.2 (2026): 440-453.

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