The programmed death-
ligands, PD-L1 and PD-L2, reside on
tumor cells and can bind with programmed death-1
protein (PD-1) on T-cells, resulting in tumor immune escape. PD-1
ligands are highly expressed in some CD30+ large cell
lymphomas, including classic
Hodgkin lymphoma (CHL), primary mediastinal large
B-cell lymphoma (PMBL), Epstein-Barr virus (EBV)-positive
diffuse large B-cell lymphoma (EBV+ DLBCL), and
anaplastic large cell lymphoma (ALCL). The genetic alteration of the chromosome 9p24.1 locus, the location of PD-L1, PD-L2, and JAK2 are the main mechanisms leading to PD-L1 and PD-L2 overexpression and are frequently observed in these CD30+ large cell
lymphomas. The JAK/STAT pathway is also commonly constitutively activated in these
lymphomas, further contributing to the upregulated expression of PD-L1 and PD-L2. Other mechanisms underlying the overexpression of PD-L1 and PD-L2 in some cases include
EBV infection and the activation of the
mitogen-activated protein kinase (MAPK) pathway. These cellular and molecular mechanisms provide a scientific rationale for
PD-1/PD-L1 blockade in treating patients with relapsed/refractory (R/R) disease and, possibly, in newly diagnosed patients. Given the high efficacy of
PD-1 inhibitors in patients with R/R CHL and PMBL, these agents have become a standard treatment in these patient subgroups. Preliminary studies of
PD-1 inhibitors in patients with R/R EBV+ DLBCL and R/R ALCL have also shown promising results. Future directions for these patients will likely include
PD-1/PD-L1 blockade in combination with other therapeutic agents, such as brentuximab or traditional
chemotherapy regimens.