PD-L1 Is Involved in the Development of Non-Hodgkin's Lymphoma by Mediating Circulating Lymphocyte Apoptosis

Abstract

Lymphocyte apoptosis plays a crucial role in tumor-induced immunosuppression. Programmed death ligand-1 (PD-L1) blocks lymphocyte activation via its receptor, PD-1. However, PD-L1/PD-1 expression and its role in enhancing immune suppression in non-Hodgkin lymphoma (NHL) have not been identified. The purpose of the study was to assess PD-L1/PD-1 expression in circulating lymphocytes in NHL and its role in immunosuppression. Twenty newly diagnosed NHL patients and twenty normal volunteers were enrolled in the study. PD-L1/PD-1 expression in circulating lymphocytes and the apoptosis of lymphocyte subsets were assessed using flow cytometry. The findings revealed that the PD-L1 expression in circulating CD3⁺, CD3⁺CD4⁺, CD3⁺CD8⁺, and CD20⁺ lymphocytes were dramatically upregulated in NHL patients (p < 0.001), whereas peripheral lymphocytes expressed low levels of PD-1. Compared with normal volunteers, a significant increase in lymphocyte apoptosis was revealed by annexin-V binding on T and B lymphocytes (p < 0.001). Peripheral lymphocytes expressing PD-L1 were four times more vulnerable to apoptosis than those expressing PD-1. Our findings imply that PD-L1 upregulation contributes to NHL development by promoting circulating lymphocyte apoptosis. This research adds to our understanding of the function of the PD-L1/PD-1 pathway in tumor evasion, establishing a novel therapeutic target in NHL. The results offer additional evidence for the immunomodulatory role of PD-L1 in circulating lymphocytes, providing a rationale for further investigations into immunological dysfunctions resulting from NHL. PD-L1⁺ lymphocytes could be employed as a biomarker to assess the effectiveness of immune systems and predict illness in patients with NHL.

Keywords: apoptosis; circulating lymphocytes; non-Hodgkin lymphoma; programmed death-ligand 1.

Figure 1

Lymphocyte apoptosis and expressions of PD-L1/PD-1 in apoptotic lymphocytes were investigated via flow cytometry: (A,B) upper-right quadrant represents gated annexin-V⁺PD-L1⁺ and annexin-V⁺PD-1⁺ lymphocytes in NHL subjects; (C,D) upper-right quadrant represents gated annexin-V⁺PD-L1⁺ and annexin-V⁺PD-1⁺ lymphocytes in normal controls; (E) diagram showing the significant difference between annexin-V, annexin-V⁺PD-L1⁺, and annexin-V⁺PD-1⁺ percentages of cells in NHL patients and normal controls. * p < 0.001.

Figure 2

ROC curves for the discrimination of NHL patients: (A) CD3⁺ percentage; (B) CD3⁺CD4⁺ percentage; (C) CD3⁺CD8⁺ percentage; (D) CD20⁺ percentage.