Surgical debulking promotes recruitment of macrophages and triggers glioblastoma phagocytosis in combination with CD47 blocking immunotherapy
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Huaiyang Zhu1,2, Lina Leiss1,5, Ning Yang3,4, Cecilie B. Rygh1, Siddhartha S. Mitra6, Samuel H. Cheshier7, Irving L. Weissman6, Bin Huang3,4, Hrvoje Miletic1,8, Rolf Bjerkvig1, Per Ø. Enger1,9, Xingang Li3,4, Jian Wang1,3,4
1Department of Biomedicine, University of Bergen, Bergen, Norway
2Department of Oncology, Shandong Chest Hospital, Jinan, China
3Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China
4Brain Science Research Institute, Shandong University, Jinan, China
5Neuro Clinic, Haukeland University Hospital, Bergen, Norway
6Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, USA
7Division of Pediatric Neurosurgery, Department of Neurosurgery, Stanford University, USA
8Department of Pathology, Haukeland University Hospital, Bergen, Norway
9Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway
Jian Wang, email: Jian.Wang@uib.no
Keywords: glioblastoma, CD47, signal regulatory protein-α, phagocytosis, macrophage
Received: April 20, 2016 Accepted: December 26, 2016 Published: January 06, 2017
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.
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