High PD-L1 Expression in HRS Cells and Macrophages in Tumor Immune Microenvironment Is Associated with Adverse Outcome and EBV Positivity in Classical Hodgkin Lymphoma

Programmed death-ligand 1 (PD-L1) on tumor cells, including Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin's lymphoma (cHL), suppresses immune responses in the tumor immune microenvironment (TME). We analyzed PD-L1 expression in macrophages and HRS cells of 98 cHL cases and correlated the findings with clinicopathological features, overall survival (OS), and progression-free survival (PFS). Epstein-Barr virus (EBV) was detected by in situ hybridization for EBV-encoded RNA. Ten high-power fields were evaluated to count the total number of macrophages and PD-L1+ macrophages, and to calculate PD-L1 histoscore (H-score) in HRS cells. EBV-positive cHL was found in 22.5% of patients. The median H-score was 80 (range 0-300). Bulky disease was associated with a lower number of PD-L1+ macrophages, and extranodal disease with a higher number (<i>p</i> = 0.05). EBV-positive cHL showed a higher PD-L1 H-score in HRS cells and a greater number of PD-L1⁺ macrophages (<i>p</i> = 0.005); both of these features, along with the proportion of PD-L1⁺ macrophages, were associated with shorter PFS and OS (<i>p</i> < 0.001). High PD-L1 expression in HRS and macrophages may be linked to worse clinical outcomes.