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Left behind but not left alone : Excluded cell populations in the non-small cell lung cancer stroma predict superior long-term overall survival

Marwitz, Sebastian ; Brunnström, Hans LU orcid ; Gulyas, Miklos ; Botling, Johan ; Reck, Martin ; Kugler, Christian ; Elfving, Hedvig ; Micke, Patrick ; Strell, Carina and Goldmann, Torsten (2026) In European Journal of Cancer 244.
Abstract

Background Non-small cell lung cancer (NSCLC) is a heterogenous disease with challenging prognosis despite clinical improvements in the last years. The tumor-microenvironment (TME) is a major factor with many cell types involved as well as distinct spatial organization. We assessed the global immune landscape and spatial architecture of excluded immune cell types within the stroma of NSCLC tissues. Methods Multiplex Immunofluorescence (mIF) staining was used to detect major immune cell lineages in tissues of 674 NSCLC patients. AI-based digital image analyses were conducted to stratify NSCLC tissues into stroma and tumor compartments as well as identify and classify single cells based on mIF marker combinations into major immune cell... (More)

Background Non-small cell lung cancer (NSCLC) is a heterogenous disease with challenging prognosis despite clinical improvements in the last years. The tumor-microenvironment (TME) is a major factor with many cell types involved as well as distinct spatial organization. We assessed the global immune landscape and spatial architecture of excluded immune cell types within the stroma of NSCLC tissues. Methods Multiplex Immunofluorescence (mIF) staining was used to detect major immune cell lineages in tissues of 674 NSCLC patients. AI-based digital image analyses were conducted to stratify NSCLC tissues into stroma and tumor compartments as well as identify and classify single cells based on mIF marker combinations into major immune cell phenotypes. Quantitative single-cell resolved immune cell phenotypes within the stroma area were used to cluster patients based on their excluded immune signature and spatial architecture and explored for impact on overall-survival. Results NSCLC stroma harbored distinct immune cell as well as spatial organizational patterns with varying combinations. Among these, a mixed immune landscape together with a stromal organization dominated by long distances to B cells and short distances to Helper T cells was associated with long-term overall-survival. This was successfully reduced to a two-variable signature comprising three different cell types, where short distances of Helper T cells to Regulatory T cells in conjunction with high B cell densities provided superior prognostic value. Conclusions The excluded immune cells within the stromal compartment are associated with strong prognostic effects based on their spatial architecture and represent a previously underappreciated cell population.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Diversity, NSCLC, Spatial biology, Stroma, Tumor microenvironment
in
European Journal of Cancer
volume
244
article number
116868
publisher
Elsevier
external identifiers
  • scopus:105042855972
  • pmid:42372636
ISSN
0959-8049
DOI
10.1016/j.ejca.2026.116868
language
English
LU publication?
yes
id
92770ab1-f76e-4d0c-8dbf-09fa09f3a080
date added to LUP
2026-09-30 14:46:28
date last changed
2026-10-01 02:20:00
@article{92770ab1-f76e-4d0c-8dbf-09fa09f3a080,
  abstract     = {{<p>Background Non-small cell lung cancer (NSCLC) is a heterogenous disease with challenging prognosis despite clinical improvements in the last years. The tumor-microenvironment (TME) is a major factor with many cell types involved as well as distinct spatial organization. We assessed the global immune landscape and spatial architecture of excluded immune cell types within the stroma of NSCLC tissues. Methods Multiplex Immunofluorescence (mIF) staining was used to detect major immune cell lineages in tissues of 674 NSCLC patients. AI-based digital image analyses were conducted to stratify NSCLC tissues into stroma and tumor compartments as well as identify and classify single cells based on mIF marker combinations into major immune cell phenotypes. Quantitative single-cell resolved immune cell phenotypes within the stroma area were used to cluster patients based on their excluded immune signature and spatial architecture and explored for impact on overall-survival. Results NSCLC stroma harbored distinct immune cell as well as spatial organizational patterns with varying combinations. Among these, a mixed immune landscape together with a stromal organization dominated by long distances to B cells and short distances to Helper T cells was associated with long-term overall-survival. This was successfully reduced to a two-variable signature comprising three different cell types, where short distances of Helper T cells to Regulatory T cells in conjunction with high B cell densities provided superior prognostic value. Conclusions The excluded immune cells within the stromal compartment are associated with strong prognostic effects based on their spatial architecture and represent a previously underappreciated cell population.</p>}},
  author       = {{Marwitz, Sebastian and Brunnström, Hans and Gulyas, Miklos and Botling, Johan and Reck, Martin and Kugler, Christian and Elfving, Hedvig and Micke, Patrick and Strell, Carina and Goldmann, Torsten}},
  issn         = {{0959-8049}},
  keywords     = {{Diversity; NSCLC; Spatial biology; Stroma; Tumor microenvironment}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{European Journal of Cancer}},
  title        = {{Left behind but not left alone : Excluded cell populations in the non-small cell lung cancer stroma predict superior long-term overall survival}},
  url          = {{http://dx.doi.org/10.1016/j.ejca.2026.116868}},
  doi          = {{10.1016/j.ejca.2026.116868}},
  volume       = {{244}},
  year         = {{2026}},
}