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

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

Pellinen, T. (författare): Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki , Helsinki, Finland

Paavolainen, L. (författare): Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki , Helsinki, Finland

Martin-Bernabe, A. (författare): Karolinska Institute,Karolinska Institutet

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Araujo, R. P. (författare): Karolinska Institute

Strell, Carina (författare): Uppsala University,Uppsala universitet,Cancerimmunterapi

Mezheyeuski, Artur (författare): Uppsala University,Uppsala universitet,Cancerprecisionsmedicin

Backman, Max, 1987- (författare): Uppsala universitet,Institutionen för immunologi, genetik och patologi

La Fleur, Linnea (författare): Uppsala universitet,Institutionen för immunologi, genetik och patologi

Bruck, O. (författare): Hematology Research Unit Helsinki, University of Helsinki and Comprehensive Cancer Center, Helsinki University Hospital , Helsinki, Finland,Helsinki University Central Hospital

Sjölund, Jonas (författare): Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Experimentell onkologi,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Experimental oncology,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments

Holmberg, Erik, 1951 (författare): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Institute of Clinical Sciences, Department of Oncology,Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital , Gothenburg, Sweden

Valimaki, K. (författare): Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki , Helsinki, Finland

Brunnström, Hans (författare): Lund University,Lunds universitet,Förbättrad diagnostik och prognostik vid lungcancer och metastaser till lunga,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Patologi, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Improved diagnostics and prognostics of lung cancer and metastases to the lungs,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Pathology, Lund,Section V,Department of Clinical Sciences, Lund,Faculty of Medicine

Botling, Johan (författare): Uppsala universitet,Cancerimmunterapi,Uppsala University Hospital

Moreno-Ruiz, P. (författare): Karolinska Institute

Kallioniemi, O. (författare): Karolinska Institutet,Science for Life Laboratory (SciLifeLab),University of Helsinki

Micke, Patrick (författare): Uppsala universitet,Cancerimmunterapi

Ostman, A. (författare): Karolinska Institute,Karolinska Institutet

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2022-09-09
2023
Engelska.
Ingår i: Jnci-Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 115:1, s. 71-82

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Background Cancer-associated fibroblasts (CAFs) are molecularly heterogeneous mesenchymal cells that interact with malignant cells and immune cells and confer anti- and protumorigenic functions. Prior in situ profiling studies of human CAFs have largely relied on scoring single markers, thus presenting a 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 was employed to spatially profile the CAF landscape in 2 population-based NSCLC cohorts (n = 636) using antibodies against 4 fibroblast markers: platelet-derived growth factor receptor-alpha (PDGFRA) and -beta (PDGFRB), fibroblast activation protein (FAP), and alpha-smooth muscle actin (alpha SMA). The CAF subsets were analyzed for their correlations with mutations, immune characteristics, and clinical variables as well as overall survival. Results Two CAF subsets, CAF7 (PDGFRA-/PDGFRB+/FAP+/alpha SMA+) and CAF13 (PDGFRA+/PDGFRB+/FAP-/alpha SMA+), showed statistically significant but opposite associations with tumor histology, driver mutations (tumor protein p53 [TP53] and epidermal growth factor receptor [EGFR]), immune features (programmed death-ligand 1 and CD163), and prognosis. In patients with early stage tumors (pathological tumor-node-metastasis IA-IB), CAF7 and CAF13 acted as independent prognostic factors. Conclusions Multimarker-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 multiplex fluorescence immunohistochemistry-based CAF profiling as a powerful tool for the discovery of clinically relevant CAF subsets.

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Av lärosätet: Göteborgs universitet; Uppsala universitet; Karolinska Institutet; Lunds universitet

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

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