DLK1: a novel target for immunotherapeutic remodeling of the tumor blood vasculature

Mol Ther. 2013 Oct;21(10):1958-68. doi: 10.1038/mt.2013.133. Epub 2013 Jul 30.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • CD8-Positive T-Lymphocytes / immunology
  • Calcium-Binding Proteins
  • Cancer Vaccines / immunology
  • Cancer Vaccines / therapeutic use*
  • Capillary Permeability
  • Carcinoma, Renal Cell / blood supply*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / therapy*
  • Cell Hypoxia
  • Cell Line, Tumor
  • Endothelial Cells / metabolism
  • Endothelial Cells / physiology
  • Female
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / immunology*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lentivirus / genetics
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Pericytes / metabolism
  • Receptors, Notch / metabolism
  • Signal Transduction
  • Tumor Microenvironment
  • Vaccines, Subunit / immunology
  • Vaccines, Subunit / therapeutic use


  • Calcium-Binding Proteins
  • Cancer Vaccines
  • Dlk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Receptors, Notch
  • Vaccines, Subunit