Abstract
Background
Tertiary lymphoid structures (TLSs) are associated with a favorable prognosis in several cancers. However, the correlation between TLSs and outcomes of esophageal squamous cell carcinoma (ESCC) and the impact of TLSs on the tumor immune microenvironment (TIME) remain unknown.
Methods
We pathologically evaluated the significance of TLSs in ESCC focusing on TLS maturation using 180 ESCC specimens and performed single-cell RNA sequencing (scRNA-seq) using 14 ESCC tissues to investigate functional differences of immune cells according to TLS presence.
Results
TLS+ cases had better recurrence-free-survival (RFS) (p < 0.0001) and overall survival (OS) (p = 0.0016) compared with TLS- cases. Additionally, mature TLS+ cases had better RFS and OS compared with immature TLS+ cases (p = 0.019 and p = 0.015) and TLS- cases (p < 0.0001 and p = 0.0002). The scRNA-seq showed that CD8+ T cells in TLS+ tumors expressed high levels of cytotoxic signatures and antigen-presentation of dendritic cells (DCs) was enhanced in TLS+ tumors. Immunohistochemistry showed that the densities of tumor-infiltrating CD8+ T cells and DCs were significantly higher in TLS+ tumors than those in TLS- tumors.
Conclusions
These data suggest the prognostic and functional significance of TLSs in ESCC and provides new insights into TLSs on the TIME.
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Data availability
The processed scRNA-seq data were deposited in the Gene Expression Omnibus (GEO, RRID: SCR_005012) database with an accession number of GSE209524.
Code availability
R script was used to analyze data and generate figures are available upon request to the corresponding authors.
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Acknowledgements
The authors thank E. Manabe and S. Sadatomi (Department of Surgery and Oncology, Kyushu University Hospital) for their expert technical assistance. The authors also thank the members of the Research Support Center and Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University for expert technical assistance. We thank Gabrielle White Wolf, Ph.D., from Edanz (https://jp.edanz.com/ac), for editing the English text of a draft of this manuscript.
Funding
This study was funded by JSPS KAKENHI (Grant Numbers JP21K08800, JP21K19530 and JP22H00480).
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SN contributed Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Visualization, Writing original draft and Writing review & editing; KO contributed Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision and Writing review & editing; MH, NK, CT, KH, SO, and YO contributed Data curation; YY contributed Data curation and Resources; CI contributed Data curation and Writing review & editing; NT contributed Resources and Software; YM, KS, and KN contributed Methodology; T.Moriyama contributed Conceptualization, Resources and Funding acquisition; T Morisaki contributed Formal analysis and Writing review & editing; YO contributed Resources and Writing review & editing; MN contributed Funding acquisition, Project administration, Supervision and Writing review & editing. All authors read and approved the final manuscript.
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The human studies were approved by Kyushu University Certified Institutional Review Board for Clinical Trials (#22002-00 and #2020-788). Study participants gave informed consent and provided written consent prior to tissue collection for scRNA-seq.
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Nakamura, S., Ohuchida, K., Hayashi, M. et al. Tertiary lymphoid structures correlate with enhancement of antitumor immunity in esophageal squamous cell carcinoma. Br J Cancer 129, 1314–1326 (2023). https://doi.org/10.1038/s41416-023-02396-7
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DOI: https://doi.org/10.1038/s41416-023-02396-7