Programmed cell death ligand 1 expression in aggressive pediatric non-Hodgkin lymphomas: frequency, genetic mechanisms, and clinical significance
Kevin E. Fisher,
Lizmery S. Ferguson,
Amy M. Coffey,
Brian Y. Merritt,
Jonathan L. Curry,
Andrea N. Marcogliese,
Angela M. Major,
Kala Y. Kamdar,
Dolores H. Lopez-Terrada,
Choladda V. Curry
Affiliations
Kevin E. Fisher
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology, Texas Children's Hospital, Houston, Texas
Lizmery S. Ferguson
Department of Pathology, Texas Children's Hospital, Houston, Texas
Amy M. Coffey
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology, Texas Children's Hospital, Houston, Texas, USA; Clinical Pathology Associates, Austin, Texas
Brian Y. Merritt
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
Jonathan L. Curry
Department of Pathology and Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Andrea N. Marcogliese
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology, Texas Children's Hospital, Houston, Texas
Angela M. Major
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
Kala Y. Kamdar
Department of Pediatrics, Baylor College of Medicine, Texas Children’s Cancer and Hematology Centers, Houston, Texas
Dolores H. Lopez-Terrada
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology, Texas Children's Hospital, Houston, Texas, USA; Department of Pediatrics, Baylor College of Medicine, Texas Children’s Cancer and Hematology Centers, Houston, Texas
Choladda V. Curry
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology, Texas Children's Hospital, Houston, Texas
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 (NHL) are limited. We assessed PD-1/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHL: 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 next-generation sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCL (11/22), 72.7% of PTLD-DLBCL (8/11), and no BL overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV positivity (P=0.033) in LBCL and lower EFS in de novo LBCL (P=0.017). NGS of select LBCL revealed distinct somatic mutations and an ultra-hypermutated 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 NHL are warranted.
