Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immunomodulatory molecules overexpressed in lymphomas and are promising immunotherapy targets for hematologic malignancies. However, studies of PD-1/PD-L1 overexpression and their clinical significance in aggressive pediatric non-Hodgkin lymphomas (NHLs) are limited. We assessed PD-1/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHLs: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL, n=8), Burkitt lymphoma (BL, n=27), and large B-cell lymphoma (LBCL) [de novo LBCL (n=22) and diffuse LBCL arising as monomorphic post-transplant lymphoproliferative disorder (PTLD-DLBCL, n=11)]. In LBCL, correlations between PD-L1 overexpression and Epstein-Barr virus (EBV) status, cell of origin, stage, nodal status, overall survival (OS), and event-free survival (EFS) were examined. The genetic mechanisms of PD-L1 overexpression were investigated using targeted nextgeneration sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCLs (11/22), 72.7% of PTLD-DLBCLs (8/11), and no BLs overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV-positivity (p=0.033) in LBCLs and lower EFS in de novo LBCL (p=0.017). NGS of select LBCLs revealed distinct somatic mutations and an ultrahypermutated PTLD-DLBCL. Most cases with 9p24.1 copy gains overexpressed PD-L1 although some cases had no discernible genetic drivers of PD-L1 overexpression. Overexpressed PD-L1 is common in pediatric LBCL, associated with EBV-positivity and 9p24.1 gains, and may have prognostic significance in de novo LBCL. Furthermore, diverse molecular mechanisms for PD-L1 overexpression in aggressive pediatric NHL can occur. Thus, additional studies exploring the therapeutic and prognostic significance and molecular mechanisms of PD-L1 overexpression in aggressive pediatric NHLs are warranted.
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