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Molecular Diagnostics

Tertiary lymphoid structure score: a promising approach to refine the TNM staging in resected non-small cell lung cancer

British Journal of Cancer volume 124, pages 1680–1689 (2021)Cite this article

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Abstract

Background

We previously proposed an immune cell score (tumour node metastasis (TNM)-Immune cell score) classifier as an add-on to the existing TNM staging system for non-small cell lung cancer (NSCLC). Herein, we examined how to reliably assess a tertiary lymphoid structure (TLS) score to refine the TNM staging system.

Methods

Using immunohistochemistry (CD8/cytokeratin), we quantified TLS in resected NSCLC whole-tumour tissue sections with three different scoring models on two independent collections (total of 553 patients). In a pilot setting, NanoString gene expression signatures were analysed for associations with TLS.

Results

The number of TLSs significantly decreased in stage III patients as compared to stage II. The TLS score was an independent positive prognostic factor, regardless of the type of (semi)-quantification strategy used (four-scale semi-quantitative; absolute count of total TLS; subpopulation of mature TLS) or the endpoint (disease-specific survival; overall survival; time to recurrence). Subgroup analyses revealed a significant prognostic impact of TLS score within each pathological stage, patient cohort and main histological subtype. Targeted gene expression analysis showed that high TLS levels were associated with the expression of B cell and adaptive immunity genes/metagenes including tumour inflammation signature.

Conclusions

The TLS score increases the prognostic power in each pathological stage and hence has the potential to refine TNM staging in resected NSCLC.

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Fig. 1: Distribution of tertiary lymphoid structures (TLS) in tissue and across TNM stages of NSCLC.
Fig. 2: Relationship between immune gene signatures and tertiary lymphoid structures (TLS).
Fig. 3: Tertiary lymphoid structures (TLS) score and clinical outcome.
Fig. 4: Inclusion of TLS in NSCLC TNM-Immune cell score (TNM-I) classifier.

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Acknowledgements

We thank Dr. Wenjie Xu at NanoString Data Analysis Service (DAS) and Anette Skogstad at Molecular Pathology Lab (UNN) for NanoString analysis assistance.

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Authors and Affiliations

  1. Department of Clinical Medicine, UiT, The Arctic University of Norway, Tromso, Norway

    Mehrdad Rakaee, Thomas K. Kilvaer, Erna-Elise Paulsen, Sigve Andersen, Roy M. Bremnes & Tom Donnem

  2. Department of Medical Biology, UiT, The Arctic University of Norway, Tromso, Norway

    Mehrdad Rakaee, Simin Jamaly, Elin Richardsen & Lill-Tove Rasmussen Busund

  3. Department of Oncology, University Hospital of North Norway, Tromso, Norway

    Thomas K. Kilvaer, Erna-Elise Paulsen, Sigve Andersen, Roy M. Bremnes & Tom Donnem

  4. Department of Clinical Pathology, University Hospital of North Norway, Tromso, Norway

    Thomas Berg, Marte Berglund, Elin Richardsen, Samer Al-Saad & Lill-Tove Rasmussen Busund

  5. Department of Oncology, Rigshospitalet, Copenhagen, Denmark

    Mette Poehl

  6. Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK

    Francesco Pezzella

  7. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    David J. Kwiatkowski

  8. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    David J. Kwiatkowski

Authors
  1. Mehrdad Rakaee
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Contributions

Conception and design: M.R. and T.D. Methodology (tissue processing, mIHC and NanoString): M.R., T.B. and M.B. Methodology (histopathology and development of immune scoring): M.R., L.-T.R.B., S.A.-S., F.P., E.R. and S.J. Clinical annotations including follow-up and tumour restaging: S.A., T.D., M.P., R.M.B. and E.-E.P. Analysis and interpretation of data: M.R. and T.K.K. Data visualisation: M.R., D.J.K. and T.K.K. Writing, review and editing: all authors. Project administration, ethical approval and funding acquisition: T.D., L.-T.R.B. and R.M.B.

Corresponding author

Correspondence to Mehrdad Rakaee.

Ethics declarations

Ethics approval and consent to participate

This study was performed in accordance with the Declaration of Helsinki. The study was ethically approved by the Regional Committee (REK) and Norwegian Data Protection Organization (REK 2016/714). The ethics committee waived the need for patient’s consent in this retrospective study.

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This manuscript does not contain any individual person’s data.

Data availability

The datasets used and analysed during this study are available from the corresponding author on reasonable request, and most of the original data are included within the article and its Supplementary Materials.

Competing interests

The authors declare no competing interests.

Funding information

This work was financially supported by Norwegian Cancer Society and the Northern Norway Health Region Authority. The funders had no role in study design, data collection/analysis, decision to publish and preparation of the manuscript.

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Rakaee, M., Kilvaer, T.K., Jamaly, S. et al. Tertiary lymphoid structure score: a promising approach to refine the TNM staging in resected non-small cell lung cancer. Br J Cancer 124, 1680–1689 (2021). https://doi.org/10.1038/s41416-021-01307-y

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