title: Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment.
abstract: Despite recent advances in radiotherapy, loco-regional failures are still the leading cause of death in many cancer patients. We have previously reported that bone marrow-derived CD11b(+) myeloid cells are recruited to tumors grown in irradiated tissues, thereby restoring the vasculature and tumor growth. In this study, we examined whether neutralizing CD11b monoclonal antibodies could inhibit the recruitment of myeloid cells into irradiated tumors and inhibit their regrowth. We observed a significant enhancement of antitumor response to radiation in squamous cell carcinoma xenografts in mice when CD11b antibodies are administered systemically. Histological examination of tumors revealed that CD11b antibodies reduced infiltration of myeloid cells expressing S100A8 and matrix metalloproteinase-9. CD11b antibodies further inhibited bone marrow-derived cell adhesion and transmigration to C166 endothelial cell monolayers and chemotactic stimuli, respectively, to levels comparable to those from CD11b knockout or CD18 hypomorphic mice. Given the clinical availability of humanized CD18 antibodies, we tested two murine tumor models in CD18 hypomorphic or CD11b knockout mice and found that tumors were more sensitive to irradiation when grown in CD18 hypomorphic mice but not in CD11b knockout mice. When CD18 hypomorphism was partially rescued by reconstitution with the wild-type bone marrow, the resistance of the tumors to irradiation was restored. Our study thus supports the rationale of using clinically available Mac-1 (CD11b/CD18) antibodies as an adjuvant therapy to radiotherapy.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: G-One
authors.initials: GO
authors.lastname: Ahn
authors.forename: Diane
authors.initials: D
authors.lastname: Tseng
authors.forename: Cho-Hwa
authors.initials: CH
authors.lastname: Liao
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Dorie
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Czechowicz
authors.forename: J Martin
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D039481:CD11b Antigen / Q000276:immunology*; D018821:CD18 Antigens / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy; D002460:Cell Line; D002465:Cell Movement; D004195:Disease Models, Animal; D006801:Humans; D016177:Macrophage-1 Antigen / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000528:radiation effects; D012008:Recurrence; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D039481:CD11b Antigen; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen
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