Takashi Sakai1, Keiju Aokage2, Shinya Neri3, Hiroshi Nakamura4, Shogo Nomura5, Kenta Tane2, Tomohiro Miyoshi2, Masato Sugano6, Motohiro Kojima4, Satoshi Fujii4, Takeshi Kuwata6, Atsushi Ochiai7, Akira Iyoda8, Masahiro Tsuboi2, Genichiro Ishii9. 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, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Division of Chest Surgery, Department of Surgery, Toho University Graduate School of Medicine, 6-11-1, Omorinishi, Ota, Tokyo, 143-8541, Japan. 2. Department of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. 3. Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, yoshidakonoe-cho, Sakyo, Kyoto, 606-8501, Japan. 4. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. 5. Biostatistics Division Center for Research Administration and Support, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. 6. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. 7. Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. 8. Division of Chest Surgery, Department of Surgery, Toho University Graduate School of Medicine, 6-11-1, Omorinishi, Ota, Tokyo, 143-8541, Japan. 9. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. Electronic address: gishii@east.ncc.go.jp.
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.
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.
Authors: Lindsey R Conroy; Josephine E Chang; Qi Sun; Harrison A Clarke; Michael D Buoncristiani; Lyndsay E A Young; Robert J McDonald; Jinze Liu; Matthew S Gentry; Derek B Allison; Ramon C Sun Journal: Adv Cancer Res Date: 2022-03-18 Impact factor: 5.767
Authors: Nina Gran Egeland; Kristin Jonsdottir; Miriam Ragle Aure; Kristine Sahlberg; Vessela N Kristensen; Deirdre Cronin-Fenton; Ivar Skaland; Einar Gudlaugsson; Jan P A Baak; Emiel A M Janssen Journal: BMC Cancer Date: 2020-05-05 Impact factor: 4.430