Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment.
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.
Ahn
G-One
GO
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Tseng
Diane
D
Liao
Cho-Hwa
CH
Dorie
Mary Jo
MJ
Czechowicz
Agnieszka
A
Brown
J Martin
JM
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
D000906:Antibodies; D039481:CD11b Antigen; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen
Blood. 1990 Mar 1;75(5):1037-50
1968349
Cancer Cell. 2005 Sep;8(3):211-26
16169466
Cancer Cell. 2008 Mar;13(3):193-205
18328424
Cancer Cell. 2009 Aug 4;16(2):91-102
19647220
IDrugs. 2000 Apr;3(4):442-6
16100700
Drugs R D. 1999 Jan;1(1):25-6
10565976
Cancer Cell. 2008 Mar;13(3):206-20
18328425
J Immunol. 1993 Apr 1;150(7):2972-80
8095957
Cancer Res. 1996 Nov 15;56(22):5150-5
8912850
Circulation. 2009 Aug 4;120(5):427-36
19620505
Biol Pharm Bull. 2008 Sep;31(9):1790-3
18758078
Nat Rev Cancer. 2007 Dec;7(12):949-60
18034185
Circulation. 1993 Oct;88(4 Pt 1):1779-87
8104739
Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12493-8
16891410
PLoS One. 2009 Aug 21;4(8):e6713
19696929
J Clin Invest. 2006 Oct;116(10):2610-21
17016557
J Immunol. 1993 Aug 1;151(3):1571-8
8101543
Blood. 2001 Apr 15;97(8):2478-86
11290613
In Vivo. 2006 Jul-Aug;20(4):431-8
16900771
J Exp Med. 2009 May 11;206(5):1089-102
19398755
J Neuropathol Exp Neurol. 2010 Feb;69(2):168-75
20084017
J Immunol. 2003 Mar 15;170(6):3233-42
12626582
Blood. 2006 Nov 15;108(10):3379-86
16857989
Radiother Oncol. 2007 Oct;85(1):7-16
17920715
Nature. 2007 Dec 6;450(7171):825-31
18064003
Int J Radiat Oncol Biol Phys. 1999 Sep 1;45(2):475-81
10487574
Diabetes. 2004 Aug;53(8):1979-86
15277376
Nat Cell Biol. 2006 Dec;8(12):1369-75
17128264
J Pathol. 2000 Oct;192(2):150-8
11004690
Microsc Res Tech. 2003 Apr 15;60(6):569-80
12645005