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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.

 

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The researchers found that two of the drug hits, ruxolitinib and PD-169316, decreased the percentage of M2-like macrophages. M2-like macrophages are known to be pro-tumorigenic and associated with poor prognosis and therapy resistance in Hodgkin lymphoma. However, only PD-169316 enhanced the percentage of M1-like macrophages, which are known to have anti-tumor activity.

The researchers validated p38 MAPK as an anti-invasion drug target using five additional drugs with a high-content imaging platform. Overall, this study provides a promising approach for identifying potential therapeutics for targeting tumor-associated macrophages in Hodgkin lymphoma.

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S7155 Batimastat (BB-94) Batimastat (BB-94) is a potent, broad spectrum matrix metalloprotease (MMP) inhibitor for MMP-1, MMP-2, MMP-9, MMP-7 and MMP-3 with IC50 of 3 nM, 4 nM, 4 nM, 6 nM and 20 nM, respectively. Also inhibits the activitity of other metalloproteases, such as ADAM17.

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