Schematic showing the mechanism of upregulation of PD-L1/2, responsible for the efficacy of the anti–PD-1 antibody pembrolizumab in primary mediastinal large B-cell and in Hodgkin lymphoma. Chromosome 9p24.1 amplification occurs commonly in these 2 disorders, leading to increased production of PD-L1/2, which in turn leads to overexpression of PD-L1/2 on the surface of the malignant cells. Another contributor to overexpression of PD-L1/2 is the JAK-STAT pathway, which when activated by different cytokines, such as interferon-γ (IFN-γ), or by overproduction of JAK2, can induce the transcription of genes that include the interferon regulatory factor 1 (IRF-1), which binds to the PD-L1/2 promoter and induces transcription and surface expression of PD-L1/2. When PD-L1/2 on the lymphoma cell surface binds with PD-1 receptor on the cytotoxic T cells, it suppresses the capacity of the immune system to attack the tumor by inactivating cytotoxic T cells. Pembrolizumab, an anti–PD-1 antibody, blocks the inactivation of the cytotoxic T cells and induces remissions mediated by the immune system. IL-6, interleukin 6.