BackgroundImmunotherapy has been shown to be a promising strategy against human cancers. A better understanding of the immune regulation in hepatocellular carcinoma (HCC) could help the development of immunotherapy against HCC. The epidermal growth factor receptor (EGFR) signaling is frequently activated in HCC and plays important roles in tumorigenesis. However, its role in HCC immunity is still largely unknown. This study aimed to investigate the impact of EGFR signaling on programmed death‐ligand 1 (PD‐L1) and human leukocyte antigen class‐I (HLA‐I) expression in HCC cells and its underlying mechanisms.MethodsThe expression of phosphorylated EGFR (p‐EGFR), PD‐L1, and HLA‐I (HLA‐ABC) in HCC specimens was detected by immunohistochemistry, and their correlations were analyzed. PD‐L1 and HLA‐ABC expression in EGFR‐activated HCC cells were detected by quantitative real‐time PCR, Western blotting, and flow cytometry, and T cell‐mediated lysis was performed to test the immunosuppressive effects of PD‐L1 and HLA‐ABC alterations in HCC cells. Furthermore, the underlying mechanisms of EGFR activation‐induced PD‐L1 up‐regulation and HLA‐ABC down‐regulation were explored by animal experiments, luciferase reporter assay, and gene gain‐ and loss‐of‐function studies.Resultsp‐EGFR was positively correlated with PD‐L1 and negatively correlated with HLA‐ABC expression in HCCs. EGFR activation by its ligand EGF up‐regulated PD‐L1 and down‐regulated HLA‐ABC in HCC cells, which was functionally important and could be abolished by the EGFR inhibitor, gefitinib, both in vitro and in vivo. Mechanistically, enhanced P38 mitogen‐activated protein kinase (MAPK) activation down‐regulated microRNA‐675‐5p (miR‐675‐5p) and up‐regulated glycolysis‐related enzyme hexokinase 2 (HK2); miR‐675‐5p down‐regulation enhanced the stability of PD‐L1 mRNA probably via the 3’‐untranslated region (3’‐UTR) of PD‐L1 and thereby caused PD‐L1 accumulation, and HK2 up‐regulation enhanced aerobic glycolysis and mediated a decrease in HLA‐ABC.ConclusionsThe EGFR‐P38 MAPK axis could up‐regulate PD‐L1 through miR‐675‐5p and down‐regulate HLA‐ABC via HK2 in HCC cells. Our study reveals a novel signaling network that may cause immune suppression in HCC and suggests that EGFR signaling can be targeted for HCC immunotherapy.

Background and objective: Tumor-associated macrophages (TAMs) play an essential role in tumor progression and metastasis. However, the role of TAMs in neoadjuvant chemotherapy (NAC) is unclear and need to be identified. The main subject of this study was to investigate whether TAMs are related to the chemotherapeutic response with triple-negative breast cancers (TNBC). Methods: We retrospectively analyzed pretreatment tissue from patients who received NAC and followed by a mastectomy or breast-conservation for stage II-III TNBC in this study. The association between TAMs and the pathological complete response (pCR) rate of TNBC to NAC was analyzed. In addition, the correlation of the TAMs with recurrence-free survival (RFS) in patients with TNBC was also evaluated. Results: Of the 91 patients, 31 (34.1%) patients experienced pathological complete response (pCR) after completion of NAC. Regarding the chemotheraptic response, patients with low infiltration of CD163 + macrophages achieved a significantly higher rate of pCR. Importantly, Kaplan-Meier survival shown that patients with high infiltration of CD163 + macrophages and non-pCR had poor OS and RFS. Conclusions: our data showed that TAMs may predict chemotherapeutic response and can be used as a promising prognostic candidate for poor survival in TNBC patients treated with NAC.

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Based on different enzyme properties in uncultured CV, different prenatal diagnostic strategies should be adopted for MPS II and Pompe disease. Combining enzyme assay and molecular studies in uncultured CV improves the reliability of prenatal diagnosis of LSDs.