A Study On The Prognostic Impacts Of PD-L1 And PD-1 Expression In Tumor Tissues And Peripheral Blood Of Patients With Invasive Non-Hodgkin Lymphoma

BackgroundNon-Hodgkin lymphoma(NHL) represents 3%-5% of all cancers. Although the survival rate of NHL improved with the application of monoclonal antibody and small molecular targeted drugs, but many of them surrendered to the disease relapse or primary drug resistance. And currently there is not standard therapy for T cell lymphoma (T-NHL). The understanding the pathogenesis of lymphoma is a key to explore new treatment strategies. PD-L1/PD-1 pathways inhibits host antitumor responses facilitating tumor immune escape. However, little is known about how this pathway function in the tumor microenvironment of lymphoma. Through study of the correlation between the expression PD-L1 and PD-1 in tumor tissues/peripheral blood and the prognosis of NHL patients, the aim of this paper is to explore the role of PD-L1/PD-1 pathways in the pathogenesis of lymphoma,Objectives1、To determine the clinicopathological impacts of PD-L1 and PD-1 expression in tumor tissues of DLBCL patients.2、To determine the clinicopathological impacts of PD-L1 and PD-1 expression in tumor tissues of T-NHL patients.3、To investigate the clinicopathological impacts of peripheral blood soluble PD-L1 (sPD-L1) and PD-1 (sPD-1) protein in the patients with invasive B-NHL.MethodsUsing immunohistochemical staining techniques, we retrospective evaluated PD-L1 and PD-1 expression in tumor tissues of 60 patients with DLBCL and 104 cases of T-NHL. plasma sPD-L1 and the sPD-1 protein were detected in 109 patients with invasive B-NHL using enzyme-linked immunosorbent assay (ELISA). And the correlation between PD-Ll/PD-1 expression and outcome of NHL patients wered compared.Results1、Some DLBCL patients had the PD-L1 and PD-1 expression in tumor tissues. PD-L1 was expressed on both tumor cells and tumor-infiltrating nonmalignant cells. In contrast, PD-1 was expressed on infiltrating lymphocyte. The prevalence rate of PD-L1+ and PD-1+DLBCL were 33%(20 cases) and 50%(30 cases), respectively. PD-L1+DLBCL was significantly associated with non-germinal center B-cell(GCB) type (P = 0.028) and low CR rate (P = 0.023). PD-L1+ DLBCL had inferior PFS (P = 0.005) and OS (P = 0.009) compared with that in patients with PD-L1-. The expression of PD-L1 maintained prognostic value for OS in multivariated analysis (HR 3.975,95% CI 3.975 1.140). Whereas PD-1 expression had no prognostic significance.2、Most T-NHL patients had PD-L1 over expression in tumor tissues.The prevalence rate of PD-L1+ T-NHL patients was 62%(65cases), which was significantly higher than that of DLBCL patients (P< 0.0001). the prevalence rate of PD-1+ T-NHL patients was 28%(29 cases), which was lower than that of DLBCL patients (P< 0.0001). The quantity of PD-L1+ cells correlated negatively with PD-1+cells (r=-0.210, P= 0.032). PD-L1+T-NHL was associated with B symptoms (P= 0.002), high IPI (P= 0.008), high PIT (P = 0.008), and ENKTCL types (P = 0.025). PD-L1+ patients had inferior PFS (P = 0.002) and OS (P= 0.001) compared with that in patients with PD-L1-. The expression of PD-L1 maintained prognostic value for OS in multivariated analysis(HR2.304,95%CI 1.245-4.262).Whereas the PD-1+patients tend to prolonged OS (P=0.067)3、Plasma soluble PD-L1 were significantly higher in invasive B-NHL than in healthy controls, the median value of 3.79 ng/ml vs 0.73 ng/ml (P< 0.0001). The sPD-L1 increases was associated with bulky mass (P=0.022) and low CR rate (P= 0.041). The high sPD-L1(cutoff of 4.57ng/ml) patients experienced a poorer PFS and OS. But no association was found between plasma sPD-L1 and tumor tissues PD-L1 expression(P=0.060). Whereas plasma sPD-1 levels was no significant difference between the patients with B-NHL and healthy controls(P = 0.105).Conclusion1、PD-L1 expression in tumor tissues was correlated with poor prognosis in DLBCL patients and might be potential therapeutic targets using PD-L1/PD-1 blockade.2、PD-L1 expression in tumor tissues was significantly higher in T-NHL than in DLBCL patients, which might be one of reasons for more invasive and poorer prognosis in T-NHL.3、High sPD-L1 patients with invasive B-NHL experienced a poorer prognosis and post-chemotherapy sPD-L1 levels was associated with treatment response. The plasma sPD-L1 was a valuable biomarker for predicting prognosis and evaluating condition of diseases.