title: DLK1: a novel target for immunotherapeutic remodeling of the tumor blood vasculature.
abstract: Tumor blood vessels are frequently inefficient in their design and function, leading to high interstitial fluid pressure, hypoxia, and acidosis in the tumor microenvironment (TME), rendering tumors refractory to the delivery of chemotherapeutic agents and immune effector cells. Here we identified the NOTCH antagonist delta-like 1 homologue (DLK1) as a vascular pericyte-associated antigen expressed in renal cell carcinomas (RCC), but not in normal kidney tissues in mice and humans. Vaccination of mice bearing established RCC against DLK1 led to immune-mediated elimination of DLK1(+) pericytes and to blood vessel normalization (i.e., decreased vascular permeability and intratumoral hypoxia) in the TME, in association with tumor growth suppression. After therapeutic vaccination, tumors displayed increased prevalence of activated VCAM1(+)CD31(+) vascular endothelial cells (VECs) and CXCL10, a type-1 T cell recruiting chemokine, in concert with increased levels of type-1 CD8(+) tumor-infiltrating lymphocytes (TIL). Vaccination against DLK1 also yielded (i) dramatic reductions in Jarid1B(+), CD133(+), and CD44(+) (hypoxia-responsive) stromal cell populations, (ii) enhanced tumor cell apoptosis, and (iii) increased NOTCH signaling in the TME. Coadministration of a γ-secretase inhibitor (N-[N-(3,5-Difluorophenacetyl-l-alanyl)]-(S)-phenylglycine t-butyl ester (DAPT)) that interferes with canonical NOTCH signaling resulted in the partial loss of therapeutic benefits associated with lentivirus encoding full-length murine (lvDLK1)-based vaccination.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Chi Sabins
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Taylor
authors.forename: Kellsye P L
authors.initials: KP
authors.lastname: Fabian
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Appleman
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Maranchie
authors.forename: Donna Beer
authors.initials: DB
authors.lastname: Stolz
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002135:Calcium-Binding Proteins; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002199:Capillary Permeability; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000235:genetics / Q000628:therapy*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D020286:Pericytes / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment; D022223:Vaccines, Subunit / Q000276:immunology / Q000627:therapeutic use
chemical_list: D002135:Calcium-Binding Proteins; D019496:Cancer Vaccines; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch; D022223:Vaccines, Subunit
references.citation: Nature. 2008 May 15;453(7193):410-4
references.pmid: 18418378
references.citation: J Histochem Cytochem. 2011 Dec;59(12):1060-75
references.pmid: 22147606
references.citation: Microcirculation. 2010 Apr;17(3):206-25
references.pmid: 20374484
references.citation: Nat Rev Cancer. 2011 Dec 15;12(1):9-22
references.pmid: 22169972
references.citation: J Natl Cancer Inst. 1973 Apr;50(4):1013-25
references.pmid: 4703766
references.citation: J Immunol. 2011 Jun 15;186(12):7006-15
references.pmid: 21593384
references.citation: Cancer Res. 2009 Mar 15;69(6):2514-22
references.pmid: 19276342
references.citation: Nat Rev Cancer. 2011 Jun;11(6):393-410
references.pmid: 21606941
references.citation: Ther Adv Med Oncol. 2012 Jul;4(4):183-94
references.pmid: 22754592
references.citation: Am J Clin Oncol. 1997 Aug;20(4):416-8
references.pmid: 9256902
references.citation: J Exp Med. 2011 Sep 26;208(10):1931-5
references.pmid: 21948802
references.citation: J Mol Med (Berl). 2008 Feb;86(2):135-44
references.pmid: 17891366
references.citation: Nat Rev Drug Discov. 2007 Sep;6(9):734-45
references.pmid: 17690708
references.citation: Int J Cancer. 2013 Apr 15;132(8):1731-40
references.pmid: 22833265
references.citation: Am J Pathol. 2002 Mar;160(3):985-1000
references.pmid: 11891196
references.citation: Cytokine. 2010 Apr;50(1):1-14
references.pmid: 20036577
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6674-82
references.pmid: 18927310
references.citation: Science. 2005 Jan 7;307(5706):58-62
references.pmid: 15637262
references.citation: J Immunol. 2012 Feb 15;188(4):1782-8
references.pmid: 22246626
references.citation: Cancer Gene Ther. 2006 Feb;13(2):131-40
references.pmid: 16096651
references.citation: Mol Ther. 2011 Apr;19(4):805-14
references.pmid: 21189473
references.citation: J Biol Chem. 2011 Mar 11;286(10):8055-8066
references.pmid: 21212269
references.citation: Cancer Res. 2011 Jul 1;71(13):4640-52
references.pmid: 21712410
references.citation: Lancet Oncol. 2009 Oct;10(10):992-1000
references.pmid: 19796751
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17898-903
references.pmid: 19815528
references.citation: Cancer Lett. 2012 May 1;318(1):26-33
references.pmid: 22142700
references.citation: Stem Cells. 2007 Aug;25(8):1954-65
references.pmid: 17478585
references.citation: Cell. 2010 May 14;141(4):583-94
references.pmid: 20478252
references.citation: Immunity. 2006 May;24(5):643-56
references.pmid: 16713981
references.citation: J Exp Med. 2010 Mar 15;207(3):491-503
references.pmid: 20194633
references.citation: Scand J Clin Lab Invest. 1954;6(4):270-6
references.pmid: 13225600
references.citation: Cancer Res. 2007 Jul 1;67(13):6451-8
references.pmid: 17616706
references.citation: Mol Cell Biol. 2006 Jul;26(14):5421-35
references.pmid: 16809777
references.citation: Biochim Biophys Acta. 2012 Jun;1822(6):988-95
references.pmid: 22353464
references.citation: J Immunol. 1987 Feb 1;138(3):989-95
references.pmid: 3100623
references.citation: J Cell Mol Med. 2012 Dec;16(12):2851-60
references.pmid: 22882758
references.citation: Int J Cancer. 2011 Nov 15;129(10):2315-27
references.pmid: 21792897
references.citation: Arterioscler Thromb Vasc Biol. 2009 May;29(5):630-8
references.pmid: 19164813
references.citation: Nat Rev Cancer. 2011 May;11(5):338-51
references.pmid: 21508972
references.citation: J Clin Oncol. 2009 Sep 1;27(25):4068-75
references.pmid: 19652072
references.citation: J Exp Med. 2012 Aug 27;209(9):1611-27
references.pmid: 22908324
references.citation: J Cell Biochem. 2007 Oct 1;102(2):301-10
references.pmid: 17647270
references.citation: Cancer Res. 2008 Oct 1;68(19):8076-84
references.pmid: 18829566
references.citation: J Clin Oncol. 2006 Dec 10;24(35):5601-8
references.pmid: 17158546
references.citation: Curr Cancer Drug Targets. 2008 Sep;8(6):447-53
references.pmid: 18781891
references.citation: Int J Cancer. 2011 Nov 1;129(9):2158-70
references.pmid: 21170961
references.citation: Ann N Y Acad Sci. 1988;532:387-94
references.pmid: 2972244
references.citation: BMC Cancer. 2012 May 29;12:201
references.pmid: 22642602
references.citation: J Neurocytol. 2002 Jul-Aug;31(6-7):423-35
references.pmid: 14501214
references.citation: Cancer Res. 2013 Apr 15;73(8):2505-17
references.pmid: 23442323