CCL17 drives fibroblast activation in the progression of pulmonary fibrosis by enhancing the TGF-ß/Smad signaling.

Pulmonary fibrosis (PF) is a type of fatal respiratory diseases with limited therapeutic options and poor prognosis. The chemokine CCL17 plays crucial roles in the pathogenesis of immune diseases. Bronchoalveolar lavage fluid (BALF) CCL17 levels are significantly higher in patients with idiopathic PF (IPF) than in healthy volunteers. However, the source and function of CCL17 in PF remain unclear. Here, we demonstrated that the levels of CCL17 were increased in the lungs of IPF patients and mice with bleomycin (BLM)-induced PF. In particular, CCL17 were upregulated in alveolar macrophages (AMs) and antibody blockade of CCL17 protected mice against BLM-induced fibrosis and significantly reduced fibroblast activation. Mechanistic studies revealed that CCL17 interacted with its receptor CCR4 on fibroblasts, thereby activating the TGF-ß/Smad signaling pathway to promote fibroblast activation and tissue fibrosis. Moreover, the knockdown of CCR4 by CCR4-siRNA or blockade by CCR4 antagonist C-021 was able to ameliorate PF pathology in mice. In summary, the CCL17-CCR4 axis is involved in the progression of PF, and targeting of CCL17 or CCR4 inhibits fibroblast activation and tissue fibrosis and may benefit patients with fibroproliferative lung diseases.

Neoadjuvant Immunotherapy Combined with Chemotherapy for Local Advanced Non-Small-Cell Lung Cancer in a Patient with a History of Breast Cancer: A Case Report.

Durvalumab consolidation therapy is the standard treatment after concurrent chemoradiotherapy for patients with surgically unresectable stage IIIA (N2) non-small-cell lung cancer (NSCLC). Neoadjuvant therapy followed by surgery could reduce locoregional and distant recurrence and improve the survival rate for surgically resectable NSCLC. However, the value of neoadjuvant therapy in locally advanced potentially resectable NSCLC remains controversial. Herein, we report a locally advanced potentially resectable NSCLC case with a history of breast cancer who achieved a pathologic complete response (pCR) after preoperative treatment with pembrolizumab and chemotherapy. A 50-year-old woman developed squamous cell carcinoma (SCC) (left lower lobe of the lung, stage IIIA-N2) after two years of chemotherapy and anti-HER2 therapy following a diagnosis of HER2-overexpressing breast cancer. Surgical resection was attempted despite an MDT classification as unamenable to curative surgical resection. After two cycles of neoadjuvant chemotherapy combined with anti-PD1 immunotherapy, the tumor significantly shrank, then the patient underwent a left lower lobectomy. Complete resection with negative margins (R0 resection) was achieved in the patient. The patient experienced grade 1-2 adverse effects and no grade 3 or worse adverse effects occurred. Cardiotoxicity did not occur in the patient despite prior anti-HER2 treatment for breast cancer. Our case study contributes to the existing evidence on the feasibility, efficacy, and safety of neoadjuvant immunotherapy combined with chemotherapy in locally advanced unresectable NSCLC. Furthermore, future studies are needed to determine which patients can benefit from immunoadjuvant therapy and the duration and course of preoperative and postoperative immunotherapy.

Inhibition of miR-7 promotes angiogenesis in human umbilical vein endothelial cells by upregulating VEGF via KLF4.

Recent lentiviral-based microRNA (miRNA) library screening has identified miRNA-7 (miR-7) as an anti­angiogenic miRNA in human umbilical vein endothelial cells (HUVECs). However, the underlying mechanism of miR-7 in the suppression of angiogenesis remains largely unknown. In the present study, we report that miR-7 inhibition promoted angiogenesis by upregulating vascular endothelial growth factor (VEGF) and directly targeting Krüppel-like factor 4 (KLF4). Downregulation of miR-7 promoted tube formation of HUVECs, accompanied by upregulation of mRNA and protein levels of both VEGF and KLF4. miR-7 directly targeted KLF4 as demonstrated by luciferase reporter assay and miR-7 mimics decreased KLF4. Furthermore, bioinformatic analysis revealed the presence of multiple DNA-binding elements of KLF4 in the VEGF promoter. Chromatin immunoprecipitation (ChIP) demonstrated that the KLF4 antibody specifically pulled down the VEGF promoter in the HUVECs. Furthermore, ectopic overexpression of KLF4 induced VEGF mRNA and protein levels. In addition, KLF4 silencing inhibited the angiogenesis induced by the miR-7 inhibitor in the HUVECs. Our results demonstrated that KLF4 is a direct target of miR-7 and a transcription activator of VEGF. These findings indicate that the miR-7-KLF4-VEGF signaling axis plays an important role in the regulation of angiogenesis in HUVECs, suggesting that miR-7 is a potential agent for the development of anti-angiogenic therapeutics in vascular diseases and solid tumors.