Targeting tumour-associated macrophages in hodgkin lymphoma using engineered extracellular matrix-mimicking cryogels

Tumour-associated macrophages are linked with poor prognosis and resistance to therapy in Hodgkin lymphoma; however, there are no suitable preclinical models to identify macrophage-targeting therapeutics. We used primary human tumours to guide the development of a mimetic cryogel, wherein Hodgkin (but not Non-Hodgkin) lymphoma cells promoted primary human macrophage invasion. In an invasion inhibitor screen, we identified five drug hits that significantly reduced tumour-associated macrophage invasion: marimastat, batimastat, AS1517499, ruxolitinib, and PD-169316. Importantly, ruxolitinib has demonstrated recent success in Hodgkin lymphoma clinical trials. Both ruxolitinib and PD-169316 (a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor) decreased the percent of M2-like macrophages; however, only PD-169316 enhanced the percentage of M1-like macrophages. We validated p38 MAPK as an anti-invasion drug target with five additional drugs using a high-content imaging platform. With our biomimetic cryogel, we modeled macrophage invasion in Hodgkin lymphoma and then used it for target discovery and drug screening, ultimately identifying potential future therapeutics. •Hodgkin lymphoma cells promote macrophage invasion and an M2-like phenotype.•JAK1/2 inhibitor ruxolitinib decreases Hodgkin lymphoma cell-induced macrophage invasion.•p38 MAPK is identified as a novel target against Hodgkin lymphoma-induced macrophage invasion.•p38 MAPK inhibitor PD-169316 repolarizes macrophages toward an M1-like phenotype.•Hodgkin lymphoma subtype dictates extracellular matrix composition of collagens, fibronectin, and glycosaminoglycans.