Enhancement of T-cell-mediated antitumor response: angiostatic adjuvant to immunotherapy against cancer.
OBJECTIVE
Tumor-released proangiogenic factors suppress endothelial adhesion molecule (EAM) expression and prevent leukocyte extravasation into the tumor. This is one reason why immunotherapy has met with limited success in the clinic. We hypothesized that overcoming EAM suppression with angiogenesis inhibitors would increase leukocyte extravasation and subsequently enhance the effectiveness of cellular immunotherapy.


METHODS
Intravital microscopy, multiple color flow cytometry, immunohistochemistry, and various tumor mouse (normal and T-cell deficient) models were used to investigate the temporal dynamics of cellular and molecular events that occur in the tumor microenvironment during tumor progression and angiostatic intervention.


RESULTS
We report that while EAM levels and T-cell infiltration are highly attenuated early on in tumor growth, angiostatic therapy modulates these effects. In tumor models with normal and T-cell-deficient mice, we show the active involvement of the adaptive immune system in cancer and differentiate antiangiogenic effects from antiangiogenic mediated enhancement of immunoextravasation. Our results indicate that a compromised immune response in tumors can be obviated by the use of antiangiogenic agents. Finally, with adoptive transfer studies in mice, we show that a phased combination of angiostatic therapy and T-cell transfer significantly (P < 0.0013) improves tumor growth inhibition.


CONCLUSIONS
This research contributes to understand the cellular mechanism of action of angiostatic agents and the immune response within the tumor microenvironment, in particular as a consequence of the temporal dynamics of EAM levels. Moreover, our results suggest that adjuvant therapy with angiogenesis inhibitors holds promise for cellular immunotherapy in the clinic.
Department of Biochemistry, The Masonic Cancer Center, University of Minnesota, Minnesota 55455, USA.
Ruud P M
RP
Dings
Kieng B
KB
Vang
Karolien
K
Castermans
Flavia
F
Popescu
Yan
Y
Zhang
Mirjam G A
MG
Oude Egbrink
Matthew F
MF
Mescher
Michael A
MA
Farrar
Arjan W
AW
Griffioen
Kevin H
KH
Mayo
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D043165:Angiostatic Proteins / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects* / Q000502:physiology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D020533:Angiogenesis Inhibitors; D043165:Angiostatic Proteins
J Clin Invest. 2005 Jun;115(6):1616-26
15931392
Int J Immunopathol Pharmacol. 2006 Oct-Dec;19(4):761-73
17166398
Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15975-80
17043243
Nat Med. 1996 Sep;2(9):992-7
8782456
Cancer Res. 2003 Jan 15;63(2):382-5
12543791
J Natl Cancer Inst. 2006 Jul 5;98(13):932-6
16818857
Nature. 2002 Dec 19-26;420(6917):860-7
12490959
J Immunol. 1993 May 15;150(10):4494-503
7683321
J Leukoc Biol. 2007 Jan;81(1):144-53
16959895
Cancer Res. 1996 Mar 1;56(5):1111-17
8640769
Acc Chem Res. 2007 Oct;40(10):1057-65
17661438
J Immunol. 2008 Sep 1;181(5):3285-90
18714000
Biochem J. 2001 Mar 1;354(Pt 2):233-42
11171099
J Biol Chem. 2001 Mar 9;276(10):7614-20
11108718
Cancer Cell. 2005 May;7(5):411-23
15894262
Nat Immunol. 2002 Nov;3(11):999-1005
12407407
J Exp Med. 2007 Jun 11;204(6):1257-65
17502665
Clin Cancer Res. 2007 Jun 1;13(11):3395-402
17545548
N Engl J Med. 2003 Jan 16;348(3):203-13
12529460
Cancer Cell. 2009 Aug 4;16(2):91-102
19647220
Cancer Lett. 2008 Jul 8;265(2):270-80
18378392
Nat Immunol. 2005 Apr;6(4):345-52
15785760
Mol Cancer Ther. 2009 Sep;8(9):2645-54
19706735
J Clin Invest. 2005 Dec;115(12):3623-33
16308572
J Exp Med. 2001 Sep 17;194(6):823-32
11560997
Blood. 1996 Jul 15;88(2):667-73
8695814
FASEB J. 2006 Apr;20(6):621-30
16581970
Cancer Res. 2001 May 15;61(10):3932-6
11358808
Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5250-5
17875752
Int J Cancer. 1999 Jan 18;80(2):315-9
9935216
Br J Cancer. 2003 Nov 17;89(10):1906-8
14612901
Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2040-5
15687502
Exp Cell Res. 2004 Oct 1;299(2):286-93
15350528
Bioconjug Chem. 2010 Jan;21(1):20-7
20020769
Clin Cancer Res. 1997 May;3(5):817-9
9815754
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
15761078
Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13132-7
16916931
Cancer Res. 2006 Nov 15;66(22):10770-7
17108113
Annu Rev Immunol. 2004;22:329-60
15032581
Int J Cancer. 2005 Jun 10;115(2):312-9
15688384
Int Immunol. 2000 May;12(5):671-6
10784613