Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma

Jun Suzuki; Keiju Aokage; Shinya Neri; Takashi Sakai; Hiroko Hashimoto; Yinghan Su; Shota Yamazaki; Hiroshi Nakamura; Kenta Tane; Tomohiro Miyoshi; Masato Sugano; Motohiro Kojima; Satoshi Fujii; Takeshi Kuwata; Atsushi Ochiai; Masahiro Tsuboi; Genichiro Ishii

doi:10.1016/j.lungcan.2020.12.020

Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma

Lung Cancer. 2021 Mar:153:1-10. doi: 10.1016/j.lungcan.2020.12.020. Epub 2020 Dec 24.

Authors

Jun Suzuki¹, Keiju Aokage², Shinya Neri³, Takashi Sakai¹, Hiroko Hashimoto⁴, Yinghan Su⁴, Shota Yamazaki⁴, Hiroshi Nakamura⁴, Kenta Tane², Tomohiro Miyoshi², Masato Sugano⁵, Motohiro Kojima⁴, Satoshi Fujii⁶, Takeshi Kuwata⁵, Atsushi Ochiai⁷, Masahiro Tsuboi², Genichiro Ishii⁸

Affiliations

¹ Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
² Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
³ Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan.
⁴ Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
⁵ Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
⁶ Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
⁷ Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
⁸ Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. Electronic address: gishii@east.ncc.go.jp.

PMID: 33429158
DOI: 10.1016/j.lungcan.2020.12.020

Abstract

Aim: Cancer-associated fibroblasts (CAFs) expressing podoplanin (PDPN) harbor a fibrous tumor microenvironment that promotes cancer progression in lung adenocarcinoma. In this study, we investigated whether tumor-promoting PDPN⁺ CAFs contribute to the immunosuppressive microenvironment in lung squamous cell carcinoma (SqCC). M&M: The gene expression profiles of immunosuppressive cytokines were compared using The Cancer Genome Atlas (TCGA) microarray lung SqCC data (n = 484) between a PDPN-high group and a PDPN-low group. Further, using patient-derived CAFs from surgically resected lung SqCC, the PDPN⁺ fraction was sorted and gene and protein expressions were analyzed. Finally, immunohistochemical staining was conducted on 131 surgically resected lung SqCC; CD8⁺ and FOXP3⁺ tumor infiltrating lymphocytes (TILs), and CD204⁺ tumor-associated macrophages (TAMs) were evaluated in cases with PDPN⁺ and PDPN^- CAFs.

Results: Analysis of TCGA database revealed that the PDPN-high group exhibited significantly higher expression of interleukin (IL)-1A, IL-1B, IL-6, IL-10, monocyte chemoattractant protein-1 (CCL2), colony stimulating factor 1 (CSF1), fibroblast growth factor 2 (FGF2), galectin 1 (LGALS1), platelet derived growth factor subunit A (PDGFA), PDGFB, and transforming growth factor-β1 (TGFB1) than those in the PDPN-low group. Among them, it was found that TGFB1 expression was higher in patient-derived PDPN⁺ CAFs. Immunohistochemical analyses revealed that more CD204⁺ TAMs infiltrated the tumor tissues in cases with PDPN⁺ CAFs than in cases with PDPN^- CAFs (P < 0.03), while CD8⁺ and FOXP3⁺ TILs did not. Furthermore, in the same tumor, CD204⁺ TAMs infiltrated more in PDPN⁺ CAF-rich areas (P = 0.005).

Conclusion: PDPN⁺ CAFs showed higher expression of TGFB1 and were associated with CD204⁺ TAM infiltration in stage-I lung SqCC, suggesting that PDPN⁺ CAFs were associated with the immunosuppressive tumor microenvironment.

Keywords: cancer associated fibroblasts; immune microenvironment; lung squamous cell carcinoma; podoplanin; tumor-associated macrophage.

Publication types

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

MeSH terms

Cancer-Associated Fibroblasts*
Carcinoma, Squamous Cell*
Fibroblasts
Humans
Lung
Lung Neoplasms* / genetics
Membrane Glycoproteins / genetics
Tumor Microenvironment

Substances

Membrane Glycoproteins