Effect Of PDL1 On The Biological Characteristics Of Esophageal Cancer Cells And Its Clinical Significance

BackgroundEsophageal cancer is one of the six common malignant tumors in the world,while the incidence of esophageal cancer in China accounts for about 49% of the total incidence of esophageal cancer in the world,which is a major malignancy that endangers the health of the people.Esophageal squamous cell carcinoma(esophageal squamous cell carcinoma,ESCC)is the most important pathological type of esophageal cancer in Asia,accounting for about 90% of the pathological types of esophageal cancer,the incidence of esophageal cancer showed a geographical distribution,mainly in rural and poor mountainous areas,is The local people's main cause of poverty and illness due to illness,but also an important factor restricting the local social and economic development.The treatment of esophageal cancer mainly by surgery,radiotherapy and chemotherapy,but the long-term treatment is not satisfactory,the quality of life of patients with very low,due to the lack of effective early prevention and treatment,most of the diagnosis of esophageal cancer is late,With the research on the mechanism of tumor immune evasion deepening,immunotherapy is considered as the most valuable new option for cancer prevention and treatment.Therefore,it is very important to find a new target involved in tumorigenesis and development.T cells require complete activation of the "double signal" and a variety of factors to participate.TCR can recognize the antigen peptide-major histocompatibility complex presented by antigen-presenting cells(APCs)and transmit the extracellular signal to intracellular,T cell activation provides the first signal,the initial activation of T cells.Costimulatory molecules on the surface of APCs bind to the corresponding ligands on the T cell surface,providing a second signal for Tcell activation that fully activates naive Tcells into effector T cells.Costimulatorymolecules include a total of three major families:the B7 family,the TNF family and the cytokine family.While B7 is the only costimulatory molecule that can deliv-ersignals to T cells via APC.Currently,the B7 family consists of seven membersintotal: B7-1(CD80),B7-2(CD86),B7h(ICOS-L),B7-H1(PD-L1),B7-DC(PD-L2)H3 and B7-H4(B7x,B7S1).Unlike other B7 family members,B7-H1 has a n-egative regulatory effect on immune responses.The gene for PDL1(programmed death-ligand 1)is located on human chromosome9q24 and encodes a 290 amino acid transmembrane protein consisting of an extracellular region of IgV and IgC-like structures,an intermediate region of hydrophobic structure,PDL1 is expressed in a variety of normal tissues,but only in the macrophage system.Studies have found that PDL1 is overexpressed in many malignancies,including non-small cell lung cancer,melanoma,Breast cancer,glioma and soon.PD1(programmed death-1PD-1 CD279)is a member of the CD28 family andconsists of extracellular segments,hydrophobic transmembrane segments,and intracellular segments.The intracellular segment contains two tyrosine residues,including immunoreceptor tyrosine-based inhibitory motif(ITIM),immunoreceptor tyrosine-based switch motif ITSM),the activation of TISM is closely related to the response activity of effector T cells.PD-1 can be expressed on the surface of activated T cells,B cells and monocytes,and also can express regulatory T cell Tregs,promote the proliferation of Treg cells,and suppress the immune response.PD1 includes two ligands PDL1 and PDL2,and PDL1 is the major ligand for PD1.Under normal physiological conditions,PD1 binds to PDL1 and then recruits tyrosine phosphatases through ITSM to dephosphorylate multiple key molecules in the TCR signaling pathway,thereby inhibiting the proliferation of T cells and exerting negative immunomodulatory effects and reducing the immune response The damage to the surrounding tissue,to avoid the occurrence of autoimmunity.Tumor cells overexpress PDL1.The activation of this signaling pathway mediates tumor immune escape andpromotes tumor growth.The specific mechanism is not fully understood and may be related to the following reasons:(1)induction of T cell tolerance;(2)induction of T cell apoptosis;(3)induction of T cell depletion;(4)enhancement of Treg cell function;Inhibit T cell proliferation.Therefore,PDL1 is expected to become a new target of tumor immunotherapy.Part ? Clinical Significance of PDL1 Expression in EsophagealSquamous Cell CarcinomaObjectiveThe aim of this study was to characterize the level of PDL1 expression and clinical significance in patients with esophageal squamous cell carcinoma(ESCC).MethodologyThe level of PDL1 protein expression in the tumor and matched adjacent tiss ues of 50 patients.The samples were determined by Western blot and immunohistoc hemistry,respectively,and its relationship with clinical pathological and prognosis wa s examined.ResultsThe level of PDL1 expression were upregulated in esophageal squamous cell carcinoma compared with adjacent noncancerous mucosa,with positive frequencies of42.0%(21/50)and 22%(11/50)(P<0.05).The levels of PDL1 expression correlated with tumor invasion depth(P<0.05)and TNM stage(P<0.05),However,there was not correlated with patient's gender,age and nodal metastasis.Kaplan-Meier survival analysis showed that upregulation of PDL1 predicted poor survival of ESCC patients with a 30 month survival rate of 38.1% compared with counterpart of 86.2%(P<0.05).ConclusionsOur results suggested that PDL1 may promote the formation and development of ESCC,and PDL1 inhibition may be a potential molecular target in treatment of ESCC.Part ? Effect of PDL1 on the biological characteristic of esophageal cancer cellsObjectiveThe aim of this study was to investigate the effect of PDL1 expression on the biological characteristics of esophageal cancer cells.Methodology1.The effects of PDL1 neutralization antibody on the proliferation of human esophageal cancer cell line EC109 cells in vitro were detected by CCK8 and flat clones.2.Scratch test and Transwell cell invasion test were used to detect the effect of PDL1 neutralizing antibody on migration and invasion of human esophageal cancer cell line EC109.3.The effect of PDL1 neutralization antibody on the proliferation of human esophageal cancer cell line EC109 cells was observed with a nude mouse subcutaneous transplantation tumor model.Results1.CCK8 experiments and flat clones showed that there was no significant difference in proliferation ability between the experimental group and the control group(P>0.05).It is suggested that the expression of PDL1 has no significant effect on the proliferation of esophageal cancer cells in vitro.2.scratch test showed that the migration ability of the experimental group was significantly lower than that of the control group,and the difference was statistically significant(P<0.05).It is suggested that the expression of PDL1 can enhance the migration ability of esophageal cancer cells.3.Transwell test showed that the invasive ability of the experimental group was significantly lower than that of the control group,and the difference was statistically significant(P<0.05).It is suggested that the expression of PDL1 can enhance the invasiveness of esophageal cancer cells.4.the experimental results of subcutaneous transplantation of nude mice showed that there was no significant difference in proliferation between the experimental group and the control group(P>0.05).It is suggested that the expression of PDL1 has no significant effect on the proliferation of esophageal cancer cells in vivo.ConclusionsPDL1 has no obvious effect on the proliferation of esophageal cancer cells in vivo and in vitro,but can enhance the migration and invasion of esophageal cancer cells.