Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma
Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma
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表达podoplanin的癌相关成纤维细胞与早期肺鳞癌免疫微环境的关系
DOI：
10.1016/j.lungcan.2020.12.020
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发表时间：
2021-01-09
期刊：
影响因子：
5.3
通讯作者：
Ishii, Genichiro
中科院分区：
文献类型：
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作者：
Suzuki, Jun;Aokage, Keiju;Ishii, Genichiro
目的：表达podoplanin（PDPN）的癌症相关成纤维细胞（CAF）具有促进肺腺癌癌症进展的纤维性肿瘤微环境。在这项研究中，我们研究了肿瘤促进PDPN+ CAF是否有助于肺鳞状细胞癌（SqCC）中的免疫抑制微环境M&M：使用癌症基因组图谱（TCGA）微阵列肺SqCC数据（n = 484）在PDPN高组和PDPN低组之间比较免疫抑制细胞因子的基因表达谱。此外，使用来自手术切除的肺SqCC的患者来源的CAF，分选PDPN+级分，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PDPN+和PDPN-CAF的病例中，评估CD 8（+）和FOXP 3（+）肿瘤浸润淋巴细胞（TIL）和CD 204（+）肿瘤相关巨噬细胞（TAM）。TCGA数据库的分析显示，PDPN-高组表现出显著更高的白细胞介素（IL）-1A，IL-1B，IL-6，IL-10，单核细胞趋化蛋白-1（CCL 2）、集落刺激因子1（CSF 1）、成纤维细胞生长因子2（FGF 2）、半乳糖凝集素1（LGALSI）、血小板衍生生长因子亚单位A（PDGFA）、PDGFB和转化生长因子-β 1（TGFBI）。其中，发现TGFBI在患者来源的PDPN+ CAF中表达更高。免疫组化结果显示，PDPN+ CAFs组中CD 204（+）TAMs的浸润率明显高于PDPN-CAFs组（P < 0.03），而CD 8（+）和FOXP 3（+）TILs的浸润率无明显差异。结论：PDPN+ CAFs在I期肺鳞癌组织中TGFB 1表达增强，且与CD 204（+）TAM浸润密切相关，提示PDPN + CAFs与免疫抑制肿瘤微环境有关。
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 (CSFI), fibroblast growth factor 2 (FGF2), galectin 1 (LGALSI), platelet derived growth factor subunit A (PDGFA), PDGFB, and transforming growth factor-beta 1 (TGFBI) than those in the PDPN-low group. Among them, it was found that TGFBI 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.