Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo.
Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.
Michael
http://orcid.org/0000-0002-7067-0689
M
Zhang
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.|Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, Stanford University School of Medicine, Stanford, California, United States of America.
Gregor
G
Hutter
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.|Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, Stanford University School of Medicine, Stanford, California, United States of America.
Suzana A
SA
Kahn
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.
Tej D
TD
Azad
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.|Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, Stanford University School of Medicine, Stanford, California, United States of America.
Sharareh
S
Gholamin
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.
Chelsea Y
CY
Xu
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
Jie
J
Liu
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.
Achal S
AS
Achrol
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.
Chase
C
Richard
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.|Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, Stanford University School of Medicine, Stanford, California, United States of America.
Pia
P
Sommerkamp
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.
Matthew Kenneth
MK
Schoen
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
Melissa N
MN
McCracken
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.|Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, Stanford University School of Medicine, Stanford, California, United States of America.
Ravi
R
Majeti
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.|Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, Stanford University School of Medicine, Stanford, California, United States of America.
Irving
I
Weissman
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.|Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, Stanford University School of Medicine, Stanford, California, United States of America.
Siddhartha S
SS
Mitra
Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California, United States of America.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.|Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, Stanford University School of Medicine, Stanford, California, United States of America.
Samuel H
SH
Cheshier
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D051928:CD47 Antigen / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D010587:Phagocytosis / Q000187:drug effects*; D010641:Phenotype
D000906:Antibodies; D051928:CD47 Antigen