Inoue Chihiro, Miki Yasuhiro, Saito Ryoko, Hata Shuko, Abe Jiro, Sato Ikuro, Okada Yoshinori, Sasano Hironobu
Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 981-8575, Japan.
Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University, Sendai, Miyagi 980-8573, Japan.
Cancers (Basel). 2019 Aug 27;11(9):1257. doi: 10.3390/cancers11091257.
Cancer-associated fibroblasts (CAFs) exert various effects upon biological behaviours of cancer. In this study, we examined the correlation of CAFs with the intra-tumoural immune system in the lung adenocarcinoma microenvironment. We studied 27 and 113 cases of lung adenocarcinoma tentatively as Cohorts 1 and 2, respectively. The patients in Cohort 1 received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for recurrent lung adenocarcinoma. -smooth muscle actin (-SMA), a surrogate marker for CAFs, was examined by immunohistochemistry. We then examined the effects of CAFs isolated from lung cancer tissues on programmed death ligand 1 (PD-L1) expression in lung adenocarcinoma cell lines. No significant associations were detected between -SMA status and the ratios of CD8/CD4 and Foxp3/CD8 in Cohort 1. However, -SMA status was significantly associated with PD-L1 status in both Cohorts 1 and 2. Conditioned medium of CAFs significantly induced PD-L1 expression in lung adenocarcinoma cell lines, A549, PC-9, and H1975. Among the cytokines examined by antibody array, C-X-C motif chemokine ligand 2 (CXCL2) increased PD-L1 mRNA expression in these cell lines. CXCL2 is therefore considered to have a potential to induce PD-L1 expression in lung adenocarcinoma cells as a result of an interaction between carcinoma cells and CAFs. These findings did firstly demonstrate that CAFs indirectly influenced tumour immunity through increasing PD-L1 expression in lung adenocarcinoma cells.
癌症相关成纤维细胞（CAFs）对癌症的生物学行为具有多种影响。在本研究中，我们检测了CAFs与肺腺癌微环境中肿瘤内免疫系统的相关性。我们分别将27例和113例肺腺癌病例初步作为队列1和队列2进行研究。队列1中的患者接受表皮生长因子受体 - 酪氨酸激酶抑制剂（EGFR - TKI）治疗复发性肺腺癌。通过免疫组织化学检测作为CAFs替代标志物的α - 平滑肌肌动蛋白（α - SMA）。然后，我们检测了从肺癌组织中分离出的CAFs对肺腺癌细胞系中程序性死亡配体1（PD - L1）表达的影响。在队列1中，未检测到α - SMA状态与CD8/CD4以及Foxp3/CD8比值之间存在显著关联。然而，在队列1和队列2中，α - SMA状态均与PD - L1状态显著相关。CAFs的条件培养基显著诱导了肺腺癌细胞系A549、PC - 9和H1975中PD - L1的表达。在通过抗体芯片检测的细胞因子中，C - X - C基序趋化因子配体2（CXCL2）增加了这些细胞系中PD - L1 mRNA的表达。因此，由于癌细胞与CAFs之间的相互作用，CXCL2被认为具有诱导肺腺癌细胞中PD - L1表达的潜力。这些发现首先证明了CAFs通过增加肺腺癌细胞中PD - L1的表达间接影响肿瘤免疫。
