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. 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.
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.
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.
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