title: Surgical debulking promotes recruitment of macrophages and triggers glioblastoma phagocytosis in combination with CD47 blocking immunotherapy.
abstract: Surgical resection is a standard component of treatment in the clinical management of patients with glioblastoma multiforme (GBM). However, experimental therapies are rarely investigated in the context of tumor debulking in preclinical models. Here, a surgical debulking GBM xenograft model was developed in nude rats, and was used in combination with CD47 blocking immunotherapy, a novel treatment strategy that triggers phagocytosis of tumor cells by macrophages in diverse cancer types including GBM. Orthotopic patient-derived xenograft tumors expressing CD47 were resected at 4 weeks after implantation and immediately thereafter treated with anti-CD47 or control antibodies injected into the cavity. Debulking prolonged survival (median survival, 68.5 vs 42.5 days, debulking and non-debulking survival times, respectively; n = 6 animals/group; P = 0.0005). Survival was further improved in animals that underwent combination treatment with anti-CD47 mAbs (median survival, 81.5 days vs 69 days, debulking + anti-CD47 vs debulking + control IgG, respectively; P = 0.0007). Immunohistochemistical staining of tumor sections revealed an increase in recruitment of cells positive for CD68, a marker for macrophages/immune cell types, to the surgical site (50% vs 10%, debulking vs non-debulking, respectively). Finally, analysis of tumor protein lysates on antibody microarrays demonstrated an increase in pro-inflammatory cytokines, such as CXCL10, and a decrease in angiogenic proteins in debulking + anti-CD47 vs non-debulking + IgG tumors. The results indicated that surgical resection combined with anti-CD47 blocking immunotherapy promoted an inflammatory response and prolonged survival in animals, and is therefore an attractive strategy for clinical translation.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Oncology, Shandong Chest Hospital, Jinan, China.
authors.forename: Huaiyang
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|Neuro Clinic, Haukeland University Hospital, Bergen, Norway.
authors.forename: Lina
authors.initials: L
authors.lastname: Leiss
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.|Brain Science Research Institute, Shandong University, Jinan, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Cecilie B
authors.initials: CB
authors.lastname: Rygh
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, USA.
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Mitra
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Stanford University, USA.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Cheshier
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, USA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.|Brain Science Research Institute, Shandong University, Jinan, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.
authors.forename: Per Ø
authors.initials: PØ
authors.lastname: Enger
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.|Brain Science Research Institute, Shandong University, Jinan, China.
authors.forename: Xingang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.|Brain Science Research Institute, Shandong University, Jinan, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D051928:CD47 Antigen / Q000276:immunology / Q000378:metabolism*; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D065426:Cytoreduction Surgical Procedures / Q000379:methods*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D010587:Phagocytosis; D011923:Rats, Nude; D016019:Survival Analysis; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; D016207:Cytokines; D018836:Inflammation Mediators
keywords: CD47; glioblastoma; macrophage; phagocytosis; signal regulatory protein-α