The Role And Evaluation Of Anlotinib And PD-1 Inhibitors In Hepatocellular Carcinoma With Portal Vein Tumor Thrombus Based On Interventional Therapy

Background and Objectives:Portal vein tumor throumbs(PVTT)is an important factor for the poor prognosis of hepatocellular carcinoma(HCC).Transcatheter arterial chemoembolization(TACE)and radiofrequency ablation(RFA)are important local treatment methods.Tyrosine kinase inhibitors(TKI)are first-line regimens,and the combined efficacy of these therapies needs to be further validated in clinical trials.Programmed death-1(PD-1)inhibitors have definite effect in advanced HCC,but the synergistic effect and mechanism between them and TKI drugs are still unclear.Currently,it is difficult for biomarker detection to accurately determine the immune efficacy or evaluate the immune response of HCC,so other predictive methods are urgently needed to evaluate the immune response.However,the unique prognostic target gene of PVTT associated with immune checkpoints at the molecular level is not yet clear.Methods:In this study,two retrospective clinical trials were conducted in PVTT-HCC patients(A:Anlotinib+TACE+RFA versus TACE+RFA;B:Anlotinib+PD-1 inhibitor+TACE+RFA versus PD-1 inhibitor+TACE+RFA)on the basis of interventional therapy to explore the clinical synergistic effect of TKI and PD-1 inhibitor on PVTT-HCC.Flow cytometry was performed to detect the peripheral immune cells and PD-1 marked T cells in some patients of clinical research.The possible synergistic mechanism and prognostic significance were explained by stratified analysis of clinical study results,and the treatment timing and possible end point of PD-1 inhibitors were interpreted from the perspective of peripheral immunity,so as to provide reference evidence for clinical decision-making.Further,bioinformatics analysis was performed to explore molecular prognostic factors specific to immune checkpoints in HCC patients with PVTT.Results:The median time to tumor progression(TTP)and overall survival time(OS)of 6 and 12 months in the Anlotinib+TACE+RFA group were better than that of 4 and 10 months in the TACE+RFA group.Anlotinib+PD-1 inhibitor+TACE+RFA compared with PD-1 inhibitor+TACE+RFA had a median TTP of 8 months and a median OS of 15 months,which were better than that of the control group(6 months and 15 months).The changes of peripheral blood lymphocytes before and after treatment were obvious:increased NK cells,decreased Tregs,and increased CD3+T,CD4+T,CD8+T cells;After 1-2 cycles of PD-1 inhibitor administration,the percentage of PD-1-labeled CD3+/CD4+/CD8+T cells in peripheral circulation decreased significantly and remained at a low level,and there was no significant correlation with subsequent PD-1 treatment.Among the specific HCC targets of PVTT,17 sites were associated with immune checkpoints.Conclusion:On the basis of interventional therapy,Anlotinib combined with PD-1 inhibitor treating HCC with PVTT has synergistic effect and might be one of the optimal clinical treatment modes.After immunotherapy,the level of peripheral immune cells in HCC patients significantly changed,and the significant increase of NK cells may be an important factor for the synergistic effect of Anlotinib combined with PD-1 inhibition.After 1-2 cycles of PD-1 inhibitor administration,some PD-1 drived effector T cells in vivo decreased significantly and remained at a low level.These significant changes can provide support for the decision of the timing and ending point of immunotherapy and serve as a prognostic evaluation factor for this comprehensive treatment mode.HCC with PVTT has unique immune checkpoint-related targets that may be potential targets or prognostic factors for immunotherapy of PVTT.