TY - JOUR
T1 - Fibroblast subsets in non-small cell lung cancer
T2 - associations with survival, mutations, and immune features
AU - Pellinen, Teijo
AU - Paavolainen, Lassi
AU - Martín-Bernabé, Alfonso
AU - Papatella Araujo, Renata
AU - Strell, Carina
AU - Mezheyeuski, Artur
AU - Backman, Max
AU - La Fleur, Linnea
AU - Brück, Oscar
AU - Sjölund, Jonas
AU - Holmberg, Erik
AU - Välimäki, Katja
AU - Brunnström, Hans
AU - Botling, Johan
AU - Moreno-Ruiz, Pablo
AU - Kallioniemi, Olli
AU - Micke, Patrick
AU - Östman, Arne
N1 - © The Author(s) 2022. Published by Oxford University Press.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1093/jnci/djac178
DO - 10.1093/jnci/djac178
M3 - Article
C2 - 36083003
SN - 1460-2105
VL - 115
SP - 71
EP - 82
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 1
ER -
