Link between tumor-promoting fibrous microenvironment and an immunosuppressive microenvironment in stage I lung adenocarcinoma. (December 2018)

• Record Type: Journal Article
• Authors: Sakai, Takashi; Aokage, Keiju; Neri, Shinya; Nakamura, Hiroshi; Nomura, Shogo; Tane, Kenta; Miyoshi, Tomohiro; Sugano, Masato; Kojima, Motohiro; Fujii, Satoshi; Kuwata, Takeshi; Ochiai, Atsushi; Iyoda, Akira; Tsuboi, Masahiro; Ishii, Genichiro
• Is Part Of: Lung cancer. Volume 126(2018)
• Page Start: 64
• Page End: 71
• Publication Date: 2018-12
• Subjects: NSCLC non-small-cell lung cancer -- CAFs cancer-associated fibroblasts -- PDPN podoplanin -- PDPN (+) CAFs PDPN-positive CAFs -- TAMs tumor-associated macrophages -- TILs tumor-infiltrated lymphocytes -- FAP fibroblast activation protein-alpha -- HE hematoxylin and eosin -- VVG verhoeff-van-Gieson -- M-CSF macrophage colony-stimulating factor -- IL interleukin -- IDO indoleamine 2, 3-dioxygenase -- TGFβ1 transforming growth factor-β1 -- VEGFA vascular endothelial growth factor A precursor -- RFS recurrence free survival; Lung adenocarcinoma -- Podoplanin -- Cancer associated fibroblasts -- Fibrous microenvironment -- Immune microenvironment; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2018.10.021
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Presence of PDPN (+) CAFs was a prognostic factor in lung adenocarcinoma (LA). PDPN (+) CAFs cases displayed a high number of CD204 (+) TAMs in cancer stroma. PDPN (+) CAFs cases displayed a low ratio of CD8/FOXP3 T cells in cancer stroma. PDPN-high LA had higher gene expression levels of immunosuppressive cytokines. LA with PDPN (+) CAFs is typified by the immunosuppressive microenvironment. Abstract: Objectives: Podoplanin-positive cancer-associated fibroblasts [PDPN (+) CAFs] play an important role in cancer progression in non-small-cell lung cancer. The aim of this study was to clarify the correlation between a fibrous microenvironment containing PDPN (+) CAFs and an immune microenvironment. Materials and methods: A total of 174 patients with pathological stage I lung adenocarcinoma were analyzed. We evaluated PDPN (+) CAFs and immune-related cells, CD 204-positive tumor-associated macrophages [CD204 (+) TAMs], CD8-positive T cells, and FOXP3-positive T cells, in cancer stroma by using immunohistochemical staining. We compared the expression levels of immune-regulatory cytokines between the PDPN high and low expression groups by analyzing the gene expression profiles of lung adenocarcinoma (n = 442). Results: Presence of PDPN (+) CAFs was a risk factor for recurrence ( P = 0.042). The number of CD204 (+) TAMs was significantly higher ( P < 0.001) and the CD8/FOXP3 T cell ratio was significantly lower in PDPN (+) CAFs cases than in PDPN (-) CAFs cases ( P = 0.027). Within the same tumor, the number of CD 204 (+) TAMs was significantly higher ( P < 0.001) and CD8/FOXP3 T cell ratio tended to be lower ( P = 0.062) in PDPN (+) CAF areas. Microarray analysis revealed that the PDPN expression-high group had significantly higher gene expression levels of cytokines that inducing M2 macrophage polarization and suppressing immune-related lymphocytes. Conclusion: The current results show that lung adenocarcinoma with PDPN (+) CAFs is typified by the immunosuppressive microenvironment, suggesting a close link between the tumor-promoting fibrous microenvironment and the immunosuppressive microenvironment.