NEDD9 promotes cancer stemness by recruiting myeloid-derived suppressor cells via CXCL8 in esophageal squamous cell carcinoma

Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy and radiotherapy failures.Myeloid-derived suppressor cells(MDSCs),in contrast,are known to be involved in mediating immunosuppression.Here,we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.Methods:ESCC tissues and cell lines were evaluated.Neural precursor cell expressed,developmentally downregulated 9(NEDD9)was knocked down and overexpressed by lentiviral transfection.Quantitative PCR,Western blot,immunohistochemistry,cell invasion,flow cytometry,cell sorting,multiplex chemokine profiling,and tumor growth analyses were performed.Results:Microarray analysis revealed 10 upregulated genes in esophageal CSCs.Only NEDD9 was upregulated in CSCs using the sphere-forming method.NEDD9 expression was correlated with tumor invasion(P=0.0218),differentiation(P=0.0153),and poor prognosis(P=0.0373).Additionally,NEDD9 was required to maintain the stem-like phenotype.Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8(CXCL8)expression via the ERK pathway.CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo.MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.Conclusions:As a marker of ESCC,NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor,suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.

Electrooxidative trifunctionalization of alkenes with N-chlorosuccinimide and ArSSAr/ArSH to α,β-dichloride arylsulfoxides

An unprecedented electrochemical oxidative trifunctionalization of olefins with diaryl disulfides/aryl thiols and N-chlorosuccinimide in an aqueous system is developed.Two C-Cl bonds,one C-S bond,and one S=O bond are produced simultaneously in one step from simple and commercially available starting materials with clean energy.This tandem methodology features as mild reaction conditions,transition metal and additional oxidant free,broad substrate scope,good functional group compatibility,and gram scale preparation.

Overcoming resistance to immunotherapy by targeting GPR84 in myeloid-derived suppressor cells

Myeloid-derived suppressor cells(MDSCs)were found to gradually accumulate in the orthotopic esophageal cancer mouse model during tumor progression.Although the roles of MDSCs in promoting tumor growth and inhibiting immune response have been extensively explored,currently,there are still no effective means for targeting MDSCs clinically.The deficiency of specific markers of MDSCs was responsible for the limited strategy to eliminating in clinic.This study identified that GPR84 was exclusively overexpressed on MDSCs.It was further found that GPR84 was prominently expressed on MDSCs in clinical samples and tumor mouse models,which drives the immunosuppression on CD8^(+)T cells by inhibiting PD-L1 degradation in lysosomes.Furthermore,G-CSF and GM-CSF were found to induce GPR84 expression through the STAT3/C/EBPβsignaling pathway.In addition,GPR84+MDSCs and PD-L1^(+)MDSCs were highly accumulated in anti-PD-1 therapy-resistant patients with esophageal cancer,and high GPR84 signature risk was verified as a negative factor for the overall survival of patients with anti-PD-1 treatment.Finally,GPR84 antagonism combined with an anti-PD-1 antibody enhanced the antitumor responses.Therefore,targeting GPR84 enhanced anti-PD-1 efficacy in esophageal cancer and other malignant tumors.This combination therapy has the potential for tumor therapy in clinics.

Myeloid cells in COVID-19 microenvironment

Varying differentiation of myeloid cells is common in tumors,inflammation,autoimmune diseases,and metabolic diseases.The release of cytokines from myeloid cells is an important driving factor that leads to severe COVID-19 cases and subsequent death.This review briefly summarizes the results of single-cell sequencing of peripheral blood,lung tissue,and cerebrospinal fluid of COVID-19 patients and describes the differentiation trajectory of myeloid cells in patients.Moreover,we describe the function and mechanism of abnormal differentiation of myeloid cells to promote disease progression.Targeting myeloid cell-derived cytokines or checkpoints is essential in developing a combined therapeutic strategy for patients with severe COVID-19.