Study On The Efficacy And Mechanism Of PD-1 Inhibitor For VEGF And CCR8 Monotherapy

Purpose:In the past few decades,PD-1(Programmed cell death 1),PD-L1(Programmed cell death 1 ligand 1)immune checkpoint inhibitors have improved treatment outcomes and overall survival in patients with advanced non-small cell lung cancer.However,less than 20% of patients benefit from monotherapy with immune checkpoint inhibitors,and most patients develop resistance.Therefore,further exploration of immunotherapy strategies that enhance antitumor activity,therapeutic efficacy,and overall survival is needed until potential curable interventions are identified.In this paper,according to the limitations of clinical application of PD-1 inhibitor,VEGF(Vascular endothelial growth factor)inhibitor and CCR8(Chemokine receptor 8)were investigated,respectively.Chemokine receptor 8 monoclonal antibody combined with PD-1 inhibitor for the efficacy of non-small cell lung cancer,providing a valuable reference for future clinical application.Method:1.Mouse A549 non-small cell lung cancer tumor model and NCI-H1299 nonsmall cell lung cancer PD-1 resistant tumor model were constructed,respectively.Blank control group,PD-1 administration group,VEGF administration group and PD-1combined with VEGF administration group were set up,and the body weight and tumor volume of mice were recorded to explore the efficacy.Then immunohistochemical methods were used to observe immune cells,markers of angiogenesis,tumor necrosis and other indicators to explore the possible mechanism.2.Immunohistochemical analysis was performed on 60 Chinese non-small cell lung cancer samples to observe the positive expression of CCR8 in tumor-associated immune cells,and histological scores were performed.Then,a mouse model of nonsmall cell lung cancer was constructed.Blank control group,PD-1 administration group,CCR8 administration group and PD-1 combined with CCR8 administration group were set up,and the weight and tumor volume of mice were recorded to explore the efficacy.Results:1.Both groups of non-small cell lung cancer models showed that the combination of VEGF inhibitor and PD-1 inhibitor significantly reduced the growth of tumor volume in mice.Immunohistochemical results showed that VEGF inhibitor combined with PD-1 inhibitor increased the expression of CD8+T cells in tumor microenvironment and perivascular,but there was no statistical difference.2.CCR8 was generally expressed in non-small cell lung cancer samples;The expression in different subtypes and gender was basically the same;The intensity of expression was significantly higher in people aged 30-50 than in people over 65.The expression level of CCR8 was significantly higher in stage Ⅲ-Ⅳ patients than in stageⅠ-Ⅱ patients.Animal models showed that PD-1 inhibitor combined with CCR8 mab significantly reduced tumor volume growth.Conclusion:1.PD-1 inhibitor combined with VEGF inhibitor can enhance the anti-tumor effect by increasing the number of CD8+T cells in tumor microenvironment or perivascular.VEGF inhibitors combined with PD-1 inhibitors have potential clinical effects in patients with PD-1 inhibitor resistance.2.CCR8 is commonly expressed in non-small cell lung cancer samples and is closely related to age and tumor stage.CCR8 MAB uses PD-1 inhibitor to increase tumor immune cell infiltration and function,enhance tumor immune response and improve tumor treatment effect by clearing T-reg.