Model of PD-1:PD-L1 Interactions in cHL. HRS cells (purple) express PD-L1 (and PD-L2) in part as a result of copy gain of chromosome 9p24.1 which includes PD-L1/PD-L2/JAK2. Tumor-associated macrophages (blue) that are in proximity to HRS cells express high levels of PD-L1, likely in response to local cytokine production, and thereby significantly increase the total amount of PD-L1 in the vicinity of the malignant cells. Both TAMs’ and HRS cells’ PD-L1 is available to bind PD-1 on CD4⁺ T cells (green) and CD8⁺ T cells (red). CD4⁺ T cells and PD-1⁺ CD4⁺ T cells are in greater numbers and are specifically enriched in the vicinity of PD-L1⁺ HRS cells compared with CD8⁺ T cells and PD-1⁺ CD8⁺ T cells and may indicate a preferential role for CD4⁺ T cells during PD-1 blockade. IFNγ, interferon-γ.