Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer

Thomas Karsten Kilvaer; Mehrdad Rakaee; Turid Hellevik; Arne Østman; Carina Strell; Roy M Bremnes; Lill-Tove Busund; Tom Dønnem; Inigo Martinez-Zubiaurre

doi:10.1371/journal.pone.0192157

Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer

PLoS One. 2018 Feb 7;13(2):e0192157. doi: 10.1371/journal.pone.0192157. eCollection 2018.

Authors

Thomas Karsten Kilvaer^{1

2}, Mehrdad Rakaee³, Turid Hellevik¹, Arne Østman⁴, Carina Strell⁴, Roy M Bremnes^{1

2}, Lill-Tove Busund^{3

5}, Tom Dønnem^{1

2}, Inigo Martinez-Zubiaurre²

Affiliations

¹ Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway.
² Department of Clinical Medicine, UiT The Artic University of Norway, Tromsø, Norway.
³ Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway.
⁴ Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Clinical Pathology, University Hospital of Northern Norway, Tromsø, Norway.

Abstract

Objectives: Selective targeting of cancer-associated fibroblasts (CAFs) has been proposed to synergize with immune-checkpoint inhibitors. While the roles of CAFs in cancer development are well described, their immune-regulatory properties remain incompletely understood. This study investigates correlations between CAF and immune-markers in tumor stroma from non-small cell lung cancer (NSCLC) patients, and examines whether a combination of CAF and immune cell scores impact patient prognosis.

Methods: Tumor specimens from 536 primary operable stage I-III NSCLC patients were organized in tissue microarrays. Expression of protein-markers was evaluated by immunohistochemistry.

Results: Fibroblast and stromal markers PDGFRα, PDGFRβ, FAP-1 and vimentin showed weak correlations while αSMA, and Masson's trichrome did not correlate with any of the investigated markers. Hierarchical clustering indicated the existence of different CAF-subsets. No relevant correlations were found between any CAF-marker and the immune-markers CD3, CD4, CD8, CD20, CD68, CD1a, CD56, FoxP3 and CD45RO. High density of fibroblast-activation protein positive mesenchymal cells (CAFFAP) was associated with better prognosis in tumors with high infiltration of CD8 and CD3 T-lymphocytes.

Conclusions: The presented data suggest that CAFs, irrespective of identity, have low influence on the degree of tumor infiltration by inflammatory- and/or immune-cells. However, CAFFAP may exert immuno-adjuvant roles in NSCLC, and targeting CAFs should be cautiously considered.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / metabolism
Cancer-Associated Fibroblasts / metabolism*
Carcinoma, Non-Small-Cell Lung / immunology
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology*
Cohort Studies
Humans
Immunophenotyping
Lung Neoplasms / immunology
Lung Neoplasms / metabolism
Lung Neoplasms / pathology*
Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism*
Survival Analysis
Tissue Array Analysis

Substances

Biomarkers, Tumor
PTPN13 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 13

Grants and funding

This work was supported by the Northern Norway Regional Health Authority with URL: https://helse-nord.no/ (grant no: SPP1137-13 to TH and SFP1138-13), the Norwegian Cancer Society with URL: https://kreftforeningen.no; (grant no: 9223 to IMZ) and Erna & Olav Aakre Foundation for Cancer Research to IMZ. The publication charges for this article have been funded by a grant from the publication fund of UiT The Arctic University of Norway. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.