PD-1/PD-L1 Pathway: A Therapeutic Target in CD30+ Large Cell Lymphomas

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.