Link between tumor-promoting fibrous microenvironment and an immunosuppressive microenvironment in stage I lung adenocarcinoma

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.

Keywords: Cancer associated fibroblasts; Fibrous microenvironment; Immune microenvironment; Lung adenocarcinoma; Podoplanin.