Abstract
CCL17 is an important chemokine that plays a vital immunomodulatory role in the tumor microenvironment (TME). Analysis of lung adenocarcinoma (LUAD) data in Kaplan–Meier plotter databases found that the overall survival of patients in the CCL17 high-expression group was higher than that of the low-expression group, especially for patients with early (stages I and II) LUAD, which has a more positive prognostic value. Expression of CCL17 in LUAD was positively correlated with the proportion of tumor-infiltrating lymphocytes, immunostimulators, and major histocompatibility complexes using the TISIDB databases. Based on the RNA-seq and clinical data of 491 LUAD patients obtained from the TCGA database, 1,455 differential genes were found between the CCL17 high- and low-expression groups. Using WGCNA analysis confirmed that the expression of differential genes in the blue module is negatively correlated with poor survival and clinical stages of LUAD patients, and CCL17 and CCR4 genes belong to the hub genes in the blue module. Further analysis by the ESTIMATE and CIBERSORT algorithm found that the naive B cells and CD8+ T cells in the CCL17 high-expression group have a higher distribution ratio in the early LUAD patients, and the high immune score has a positive relationship with the overall survival rate. Using somatic mutation data of TCGA-LUAD, we found that 1) the tumor mutation burden values of the CCL17 high-expression group were significantly lower than those of the CCL17 low-expression group and 2) the expression levels of CCL17 and the tumor mutation burden values were negatively correlated. Transwell chemotaxis and cytotoxicity assays confirmed that CCL17 contributes to the migration of CCR4-positive lymphocytes into the H1993 LUAD TME and enhances the specific lysis of LUAD cells. In summary, high expression of CCL17 in the LUAD TME promotes local immune cell infiltration and antitumor immune response, which may contribute to the better survival and prognosis of patients with early LUAD.
Highlights
The tumor microenvironment (TME) is the internal environment in which tumor cells produce and live (Hanahan and Coussens, 2012)
With further studies on clinical characteristics of lung cancer patients, we found that CCL17 mainly affected the survival status of early-stage lung cancer patients
CCL17 high expression had a positive effect on the prognosis of lung cancer patients in T1 (OS, hazard ratio (HR) = 0.63 (0.46–0.86), p = 0.0029; progression-free survival (PFS), HR = 0.39 (0.24–0.65),p = 0.0002), N0 (OS, HR = 0.73 (0.53–0.93), p = 0.012; PFS, HR = 0.7 (0.49–0.98),p = 0.0366), N1 (OS, HR = 0.72 (0.5–0.99), p = 0.0445), and M0 (OS, HR = 0.68 (0.54–0.87), p = 0.0015) but was not associated with overall survival (OS) and PFS in T2, T4, and N2 stages and PFS in N1 and M0 stages
Summary
The tumor microenvironment (TME) is the internal environment in which tumor cells produce and live (Hanahan and Coussens, 2012). The TME includes the tumor cells and the fibroblasts, immune and inflammatory cells, glial cells, and other cells around them (Mlecnik et al, 2018), of which chemokines are an important category (Gregorio et al, 2018). Chemokines are a group of small-molecule-secreted proteins that have chemotactic effects and a variety of biological effects on different target cells. CCL17 belongs to the CC subfamily and plays an effective role in chemotaxis of CCR4+ T lymphocytes through the CCR4 receptor molecule (Viola et al, 2012). When chemokines interact with chemokine receptors, different immune cell subsets can be recruited into the TME, and these cell subsets play an important role in tumor development and therapeutic prognosis (Yoshie and Matsushima, 2015)
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