The Clinical and Biological Effects of PD-1 Expression on Tumor Cells in Diffuse Large B-Cell Lymphoma

Abstract

The clinical and biological significance of programmed death-1 (PD-1) expression by B-lymphoma cells is largely unknown. Here, using multicolor immunofluorescent staining (MC-IF), we investigated PD-1 and PD-L1 expression in PAX5+ (B-lymphoma), CD68+ (macrophage), or CD3+ (T-cell) cells in formalin-fixed, paraffin-embedded samples of 32 consecutive patients with de novo diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus chemotherapy. PD-1- and PD-L1-expressing PAX5+ cells were observed in 59% and 3% of the patients, respectively. PD-1-expressing CD3+ lymphocytes and PD-L1-expressing CD68+ macrophages were observed in 89% and 86% of the patients, respectively. PD-L1 expression on PAX5+ lymphoma cells or CD68+ macrophages and PD-1 expression on CD3+ lymphocytes were not correlated with prognosis. However, patients with PD-1 expression on lymphoma cells showed shorter progression-free survival than those lacking PD-1-expressing lymphoma cells (p = 0.033). Furthermore, genetically modified PD-1-knockout human B-lymphoma VAL cells showed reduced cell growth and migration, and decreased S6 kinase phosphorylation than VAL/mock cells. Our data suggest that PD-1 expression on DLBCL cells detected by MC-IF was associated with poor prognosis and cell-intrinsic PD-1 signaling was related with cell growth and migration in a subpopulation of B-cell lymphoma. These findings may allow the development of distinct DLBCL subtypes affecting prognosis.

Keywords

• programmed death-1
• programmed death-ligand 1
• diffuse large B-cell lymphoma
• clustered regularly interspaced short palindromic repeats-Cas9
• tumor-associated macrophages
• nivolumab