| Background and Objectives:1.Previous studies indicated that co-infusion of cord blood cells may potentially improve the outcome of haploidentical donor transplantation.In this study,we analyzed the clinical efficacy of haploidentical donor transplantation supported by third-party umbilical cord blood and HLA-matched unrelated donor transplantation in the treatment of hematological malignancies.2、Patients with leukemia recurrence after Allo-HSCT have a poor prognosis and limited treatment options.Immune failure is an important reason for the failure of treatment of hematological malignancies after Allo-HSCT.PD-1,as a negative costimulatory molecule,participates in the immune escape of tumor cells.Immune checkpoint blocking(ICB)therapy is a potential therapeutic strategy to improve the anti-tumor effect of Allo-HSCT.It is reported that PD-1 inhibitors have a higher response rate in patients with recurrent disease,but the risk of severe GVHD is increased.This study analyzed the dynamic expression of PD-1 on T cell subsets in peripheral blood(PB)and bone marrow(BM)after Allo-HSCT,and then explored its expression characteristics and clinical significance,so as to provide a theoretical guidance for the treatment of ICB after transplantation.Methods:1.The clinical data of 40 patients with HID supported by third-party umbilical cord blood and 26 patients with URD were retrospectively analyzed.The differences of hematopoietic reconstitution time,incidence of acute and chronic GVHD,other complications,OS,PFS,recurrence rate and mortality between the two groups were analyzed.2.PB and BM samples were collected from 30 patients with hematological malignancies at 1,3,6,9 and 12 months after Allo-HSCT.The PB and BM fluid of 15 age-and sex-matched healthy volunteers and 15 patients with non-hematological malignancies were taken as the control group.The expression levels of PD-1 and TIM-3,LAG-3,TIGIT and KLRG1 in CD4+ and CD8+T cells were monitored by flow cytometry dynamically.The expression characteristics and clinical significance of PD-1 and other inhibitory receptors on T cells after transplantation were statistically analyzed.3.To study the function of CD8+T cells co-expressing PD-1 and PD-1 with different inhibitory receptors,including cytokine release,proliferation,cytotoxicity and apoptosis detection.Results:1.The characteristics of patients in the two groups were similar,there were no significant differences in age,gender,type of disease,disease status before transplantation,gender matching and blood type matching between donors and recipients.2.The incidences of II~IV grade acute and chronic GVHD were similar in the two groups.There was no significant difference in the incidence of other complications including bacterial infection,fungal infection,cytomegalovirus infection,hemorrhagic cystitis and hepatic vein occlusive disease between the two groups.3.The 2-year OS in HID and URD group were 84.7±5.8%,69.2±9.1(P=0.13);PFS were 74.0±8.1%,47.1±13.4%(P=0.10);NRM were 10.0%,19.2%(P=0.31);2-year cumulative incidence of relapse were 7.5%,21.9%(P=0.08),respectively.Multivariate analysis demonstrated that the relapse risk in HID group was significantly lower than in URD group(P=0.039).Moreover,HID group have prolonged PFS.4.The expression of PD-1 on CD4+ and CD8+ T cells in BM and PB after transplantation was significantly higher than control group,and the time of transplantation was negatively correlated with the expression of PD-1.The expression level of PD-1 in CD4+T cells was significantly higher than control group at all time points,while the expression level of PD-1 in CD8+T cells was significantly higher than control group only 1 to 6 months after transplantation.5.After transplantation,the expression of CD27 and CD28 on CD4+T cells and CD8+T cells decreased,while the expression of ICOS was not significantly different from that of the control group.At all time points in the study,the expression of TIGIT on bone marrow CD8+T cells after transplantation was significantly up-regulated,but the expression on CD4+T cells was not significantly different from that in the control group,and TIM-3 was only temporarily up-regulated on the surface of T cells.There was no significant difference in the expression of LAG-3 and KLRG1 between transplantation and control group.6.The cytokine production and the expression of Ki-67 of PD-1+CD8+T cells was significantly lower than PD-1-CD8+T cells,and the apoptosis rate increased significantly,but there was no significant difference in the expression levels of perforin and granzyme B.The co-expression of PD-1 and TIM-3or TIGIT will further reduce the function of CD8+T cells.7.Multivariate linear regression analysis showed that there was a significant correlation between CMV infection and down-regulated expression of PD-1 on T cells.8.The expression of PD-1 on T cells in patients with acute GVHD decreased slightly,chronic GVHD was associated with the decreased expression of PD-1 on CD8+T cells.9.The expression level of PD-1 and TIGIT of CD8+T cells in recurrent patients after transplantation was significantly higher than that in patients with CR,but there was no significant difference in the expression level of TIM-3 between the two groups.In addition,PD-1+TIGIT+CD8+T cells accumulated in bone marrow of patients with relapse,which was significantly higher than that in patients with CR.Conclusions: 1.Haploidentical donor ransplantation supported by third-party umbilical cord blood results in better outcomes with HLA-matched unrelated donor transplantation in the treatment of hematological malignant diseases,so it might be a favourable alternative to a HLA-matched unrelated donor transplantation.2.The expression of PD-1 on CD4+ and CD8+ T cells showed different dynamic changes after Allo-HSCT.3.PD-1+CD8+T cells show exhausted phenotypic characteristics and functional impairment,suggesting that PD-1 plays an important role in T cell failure after transplantation.4.The co-expression of PD-1 and TIGIT or TIM-3 showed a synergistic inhibitory effect on the function of CD8+T cells.5.CMV infection after transplantation is a clinical factor closely related to the decreased expression of PD-1on T cells.6.There was no significant correlation between acute GVHD and the expression of PD-1 on T cells,but chronic GVHD was related to the decreased expression of PD-1 on CD8+T cells.7.The up-regulated expression of PD-1 and TIGIT is closely related to the recurrence of AML after transplantation,which may play a role in the disease progression of AML after transplantation. |
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