表达血小板内皮细胞黏附分子的癌症相关成纤维细胞与早期肺鳞状细胞癌免疫微环境之间的关系
Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma.
作者信息
Suzuki Jun, Aokage Keiju, Neri Shinya, Sakai Takashi, Hashimoto Hiroko, Su Yinghan, Yamazaki Shota, Nakamura Hiroshi, Tane Kenta, Miyoshi Tomohiro, Sugano Masato, Kojima Motohiro, Fujii Satoshi, Kuwata Takeshi, Ochiai Atsushi, Tsuboi Masahiro, Ishii Genichiro
机构信息
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.
Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
出版信息
Lung Cancer. 2021 Mar;153:1-10. doi: 10.1016/j.lungcan.2020.12.020. Epub 2020 Dec 24.
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.
目的
表达血小板反应蛋白-1（PDPN）的癌症相关成纤维细胞（CAFs）具有促进肺腺癌癌症进展的纤维性肿瘤微环境。在本研究中，我们调查了具有促肿瘤作用的PDPN CAFs是否促成肺鳞状细胞癌（SqCC）的免疫抑制微环境。材料与方法：利用癌症基因组图谱（TCGA）肺SqCC微阵列数据（n = 484），比较了PDPN高表达组和PDPN低表达组免疫抑制细胞因子的基因表达谱。此外，使用手术切除的肺SqCC患者来源的CAFs，分选PDPN组分并分析基因和蛋白质表达。最后，对131例手术切除的肺SqCC进行免疫组织化学染色；在有PDPN和PDPN CAFs的病例中评估CD8和FOXP3肿瘤浸润淋巴细胞（TILs）以及CD204肿瘤相关巨噬细胞（TAMs）。
结果
对TCGA数据库的分析显示，PDPN高表达组白细胞介素（IL）-1A、IL-1B、IL-6、IL-10、单核细胞趋化蛋白-1（CCL2）、集落刺激因子1（CSF1）、成纤维细胞生长因子2（FGF2）、半乳糖凝集素1（LGALS1）、血小板衍生生长因子亚基A（PDGFA）、PDGFB和转化生长因子-β1（TGFB1）的表达明显高于PDPN低表达组。其中，发现患者来源的PDPN CAFs中TGFB1表达更高。免疫组织化学分析显示，与无PDPN CAFs的病例相比，有PDPN CAFs的病例中更多CD204 TAMs浸润肿瘤组织（P < 0.03），而CD8和FOXP3 TILs则不然。此外，在同一肿瘤中，CD204 TAMs在富含PDPN CAF的区域浸润更多（P = 0.005）。
结论
PDPN CAFs在I期肺SqCC中显示出更高的TGFB1表达，并与CD204 TAM浸润相关，提示PDPN CAFs与免疫抑制性肿瘤微环境相关。
Zotero 插件