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Spatial distribution of tertiary lymphoid structures in the molecular and clinical context of non-small cell lung cancer

Elfving, Hedvig ; Yu, Hui ; Fessehatsion, Kaleab Kassete ; Brunnström, Hans LU orcid ; Botling, Johan ; Gulyas, Miklos ; Backman, Max ; Lindberg, Amanda ; Strell, Carina and Micke, Patrick (2025) In Cellular Oncology 48(3). p.801-813
Abstract

Introduction: Tertiary lymphoid structures (TLS) are lymphocyte aggregates resembling secondary lymphoid organs and are pivotal in cancer immunity. The ambiguous morphological definition of TLS makes it challenging to ascertain their clinical impact on patient survival and response to immunotherapy. Objectives: This study aimed to characterize TLS in hematoxylin-eosin tissue sections from lung cancer patients, assessing their occurrence in relation to the local immune environment, mutational background, and patient outcome. Methods: Two pathologists evaluated one whole tissue section from resection specimens of 680 NSCLC patients. TLS were spatially quantified within the tumor area or periphery and further categorized based on the... (More)

Introduction: Tertiary lymphoid structures (TLS) are lymphocyte aggregates resembling secondary lymphoid organs and are pivotal in cancer immunity. The ambiguous morphological definition of TLS makes it challenging to ascertain their clinical impact on patient survival and response to immunotherapy. Objectives: This study aimed to characterize TLS in hematoxylin-eosin tissue sections from lung cancer patients, assessing their occurrence in relation to the local immune environment, mutational background, and patient outcome. Methods: Two pathologists evaluated one whole tissue section from resection specimens of 680 NSCLC patients. TLS were spatially quantified within the tumor area or periphery and further categorized based on the presence of germinal centers (mature TLS). Metrics were integrated with immune cell counts, genomic and transcriptomic data, and correlated with clinical parameters. Results: TLS were present in 86% of 536 evaluable cases, predominantly in the tumor periphery, with a median of eight TLS per case. Mature TLS were found in 24% of cases. TLS presence correlated positively with increased plasma cell (CD138+) and lymphocytic cell (CD3+, CD8+, FOXP3+) infiltration. Tumors with higher tumor mutational burden exhibited higher numbers of peripheral TLS. The overall TLS quantity was independently associated with improved patient survival, irrespective of TLS maturation status. This prognostic association held true for peripheral TLS but not for tumor TLS. Conclusion: TLS in NSCLC is common and their correlation with a specific immune phenotype suggests biological relevance in the local immune reaction. The prognostic significance of this scoring system on routine hematoxylin-eosin sections has the potential to augment diagnostic algorithms for NSCLC patients.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Immune microenvironment, Immunotherapy, Lymphocytes, Prognosis, Tumor microenvironment
in
Cellular Oncology
volume
48
issue
3
pages
13 pages
publisher
Springer Science and Business Media B.V.
external identifiers
  • scopus:86000200156
  • pmid:40029549
ISSN
2211-3428
DOI
10.1007/s13402-025-01052-x
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2025.
id
cdf32a0a-f2c1-4a69-a840-4e5908f042a2
date added to LUP
2025-06-24 14:34:36
date last changed
2025-06-25 03:00:04
@article{cdf32a0a-f2c1-4a69-a840-4e5908f042a2,
  abstract     = {{<p>Introduction: Tertiary lymphoid structures (TLS) are lymphocyte aggregates resembling secondary lymphoid organs and are pivotal in cancer immunity. The ambiguous morphological definition of TLS makes it challenging to ascertain their clinical impact on patient survival and response to immunotherapy. Objectives: This study aimed to characterize TLS in hematoxylin-eosin tissue sections from lung cancer patients, assessing their occurrence in relation to the local immune environment, mutational background, and patient outcome. Methods: Two pathologists evaluated one whole tissue section from resection specimens of 680 NSCLC patients. TLS were spatially quantified within the tumor area or periphery and further categorized based on the presence of germinal centers (mature TLS). Metrics were integrated with immune cell counts, genomic and transcriptomic data, and correlated with clinical parameters. Results: TLS were present in 86% of 536 evaluable cases, predominantly in the tumor periphery, with a median of eight TLS per case. Mature TLS were found in 24% of cases. TLS presence correlated positively with increased plasma cell (CD138+) and lymphocytic cell (CD3+, CD8+, FOXP3+) infiltration. Tumors with higher tumor mutational burden exhibited higher numbers of peripheral TLS. The overall TLS quantity was independently associated with improved patient survival, irrespective of TLS maturation status. This prognostic association held true for peripheral TLS but not for tumor TLS. Conclusion: TLS in NSCLC is common and their correlation with a specific immune phenotype suggests biological relevance in the local immune reaction. The prognostic significance of this scoring system on routine hematoxylin-eosin sections has the potential to augment diagnostic algorithms for NSCLC patients.</p>}},
  author       = {{Elfving, Hedvig and Yu, Hui and Fessehatsion, Kaleab Kassete and Brunnström, Hans and Botling, Johan and Gulyas, Miklos and Backman, Max and Lindberg, Amanda and Strell, Carina and Micke, Patrick}},
  issn         = {{2211-3428}},
  keywords     = {{Immune microenvironment; Immunotherapy; Lymphocytes; Prognosis; Tumor microenvironment}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{801--813}},
  publisher    = {{Springer Science and Business Media B.V.}},
  series       = {{Cellular Oncology}},
  title        = {{Spatial distribution of tertiary lymphoid structures in the molecular and clinical context of non-small cell lung cancer}},
  url          = {{http://dx.doi.org/10.1007/s13402-025-01052-x}},
  doi          = {{10.1007/s13402-025-01052-x}},
  volume       = {{48}},
  year         = {{2025}},
}