Fig. 1

The tumor microenvironment in classical HL and proposed effects of combined JAK and PD1 inhibition. a HL tumor microenvironment: suppressed state of effector cells. HRS cells attract various immune cells into the tumor tissue. Effector CD8 T cells, NK cells, and (cytotoxic) CD4 T cells, which potentially could eliminate HRS cells, are silenced by various mechanisms, including PD-L1 expression by HRS cells, tumor-associated macrophages (TAM), and also MDSC. MDSC suppress these effector cells also by additional means. CD8 T cells are mostly incapable of attacking HRS cells, as these, in the majority of cases, have lost MHC class I expression, which is essential for CD8 T cells to recognize their targets with their T cell receptor (TCR). STAT signaling is essential for the survival of HRS cells, and there is an indication that reverse signaling through PD-L1 also supports the survival of HRS cells. b Proposed effects of combined JAK1/2 and PD1/PD-L1 inhibition. Inhibition of JAK blocks signaling and alters gene expression programs in various infiltrating immune cells, including MDSC, resulting in inhibited suppressor activity. JAK inhibition may also directly kill HRS cells. It seems that inhibition of effector cell functions is less affected by JAK inhibition. The addition of an anti-PD1 antibody to JAKi blocks the PD-L1/PD1 axis, reactivating antitumor cell effector cells and the elimination of HRS cells. It is not yet clear which effector cells are mainly responsible for the elimination of the HRS cells. Inhibition of PD-L1/PD1 signaling may also contribute to HRS cell killing by impairing reverse signaling through PD-L1 into the HRS cells. Generated with BioRender