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

Laura C Bahlmann; Chang Xue; Allysia A Chin; Arianna Skirzynska; Joy Lu; Brigitte Thériault; David Uehling; Yulia Yerofeyeva; Rachel Peters; Kela Liu; Jianan Chen; Anne L Martel; Martin Yaffe; Rima Al-Awar; Rashmi S Goswami; Jarkko Ylanko; David W Andrews; John Kuruvilla; Rob C Laister; Molly S Shoichet

doi:10.1016/j.biomaterials.2023.122121

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

Biomaterials. 2023 Jun:297:122121. doi: 10.1016/j.biomaterials.2023.122121. Epub 2023 Apr 9.

Authors

Laura C Bahlmann¹, Chang Xue¹, Allysia A Chin², Arianna Skirzynska³, Joy Lu¹, Brigitte Thériault⁴, David Uehling⁴, Yulia Yerofeyeva⁵, Rachel Peters⁵, Kela Liu⁵, Jianan Chen⁶, Anne L Martel⁷, Martin Yaffe⁷, Rima Al-Awar⁸, Rashmi S Goswami⁹, Jarkko Ylanko¹⁰, David W Andrews¹¹, John Kuruvilla¹², Rob C Laister¹³, Molly S Shoichet¹⁴

Affiliations

¹ Institute of Biomedical Engineering, 164 College Street, Toronto, Ontario, M5S 3G9, Canada; The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada.
² The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario, M5S 3E5, Canada.
³ Institute of Biomedical Engineering, 164 College Street, Toronto, Ontario, M5S 3G9, Canada; The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario, M5S 3E5, Canada.
⁴ Drug Discovery Program, Ontario Institute of Cancer Research, 661 University Ave Suite 510, Toronto, Ontario, M5G 0A3, Canada.
⁵ Biomarker Imaging Research Laboratory, Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada.
⁶ Department of Medical Biophysics, University of Toronto, 101 College St Suite 15-701, Toronto, Ontario, M5G 1L7, Canada.
⁷ Department of Medical Biophysics, University of Toronto, 101 College St Suite 15-701, Toronto, Ontario, M5G 1L7, Canada; Physical Sciences, Odette Cancer Research Program, Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada.
⁸ Drug Discovery Program, Ontario Institute of Cancer Research, 661 University Ave Suite 510, Toronto, Ontario, M5G 0A3, Canada; Department of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
⁹ Biological Sciences, Odette Cancer Research Program, Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada; Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada.
¹⁰ Biological Sciences, Odette Cancer Research Program, Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada.
¹¹ Department of Medical Biophysics, University of Toronto, 101 College St Suite 15-701, Toronto, Ontario, M5G 1L7, Canada; Biological Sciences, Odette Cancer Research Program, Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada; Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada.
¹² Princess Margaret Cancer Centre, University Health Network, 610 University Ave, Toronto, Ontario, M5G 2C1, Canada.
¹³ Princess Margaret Cancer Centre, University Health Network, 610 University Ave, Toronto, Ontario, M5G 2C1, Canada. Electronic address: [email protected].
¹⁴ Institute of Biomedical Engineering, 164 College Street, Toronto, Ontario, M5S 3G9, Canada; The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario, M5S 3E5, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6, Canada. Electronic address: [email protected].

PMID: 37075613
DOI: 10.1016/j.biomaterials.2023.122121

Abstract

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.

Keywords: Drug screening; Extracellular matrix; Hodgkin lymphoma; Invasion; Ruxolitinib; Tumour-associated macrophages.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cryogels
Extracellular Matrix / metabolism
Hodgkin Disease* / drug therapy
Hodgkin Disease* / pathology
Humans
Tumor-Associated Macrophages* / metabolism
Tumor-Associated Macrophages* / pathology
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

ruxolitinib
Cryogels
p38 Mitogen-Activated Protein Kinases

Grants and funding

CIHR/Canada