Fibroblast subsets in non-small cell lung cancer: associations with survival, mutations, and immune features

Teijo Pellinen, Lassi Paavolainen, Alfonso Martín-Bernabé, Renata Papatella Araujo, Carina Strell, Artur Mezheyeuski, Max Backman, Linnea La Fleur, Oscar Brück, Jonas Sjölund, Erik Holmberg, Katja Välimäki, Hans Brunnström, Johan Botling, Pablo Moreno-Ruiz, Olli Kallioniemi, Patrick Micke, Arne Östman

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Cancer-associated fibroblasts (CAFs) are molecularly heterogeneous mesenchymal cells that interact with malignant cells and immune cells and confer both anti- and pro-tumorigenic functions. Prior in situ profiling studies of human CAFs have largely relied on scoring single markers, thus presenting a very limited view of their molecular complexity. Our objective was to study the complex spatial tumor microenvironment of non-small cell lung cancer (NSCLC) with multiple CAF biomarkers, identify novel CAF subsets and explore their associations with patient outcome.

METHODS: Multiplex fluorescence immunohistochemistry (mfIHC) was employed to spatially profile the CAF landscape in two population-based NSCLC cohorts (n = 636) using antibodies against four fibroblast markers: Platelet-derived growth factor receptor-alpha (PDGFRA) and -beta (PDGFRB), fibroblast activation protein (FAP), and alpha-smooth muscle actin (αSMA). The CAF subsets were analyzed for their correlations with mutations, immune characteristics, clinical variables as well as overall survival (OS).

RESULTS: Two CAF subsets, CAF7 (PDGFRA-/PDGFRB+/FAP+/αSMA+) and CAF13 (PDGFRA+/PDGFRB+/FAP-/αSMA+), showed significant but opposite associations with tumor histology, driver mutations (TP53 and EGFR), immune features (PD-L1 and CD163), and prognosis. In patients with early-stage tumors (pTNM IA-IB), CAF7 and CAF13 acted as independent prognostic factors.

CONCLUSIONS: Multi-marker-defined CAF subsets were identified through high-content spatial profiling. The robust associations of CAFs with driver mutations, immune features, and outcome suggest CAFs as essential factors in NSCLC progression and warrant further studies to explore their potential as biomarkers or therapeutic targets. This study also highlights mfIHC-based CAF profiling as a powerful tool for the discovery of clinically relevant CAF subsets.

Original languageEnglish
Pages (from-to)71-82
JournalJournal of the National Cancer Institute
Issue number1
Early online date2022 Sept 9
Publication statusPublished - 2023

Bibliographical note

© The Author(s) 2022. Published by Oxford University Press.

Subject classification (UKÄ)

  • Cancer and Oncology


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