Vascular Normalization, T Cell Trafficking and Anti-tumor Immunity

  • Kellsye L. Fabian
  • Walter J. StorkusEmail author
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 9)


Improved understanding of the role of the immune system to limit tumor establishment and progression has led to the development and refinement of targeted immunotherapies. Treatments, such as cancer vaccines, CAR T cells and immune checkpoint inhibitors, aim to activate and harness T cells against cancer. However, tumors induce pathological angiogenesis and, at the same time, condition the tumor blood vessels to form a tumor vascular network that is highly abnormal. As a consequence, activated tumor- and stroma-specific T cells may be impeded from penetrating into the tumor lesions, greatly obstructing the therapeutic efficacy of such therapies. Hence, approaches designed to normalize the tumor vasculature are essential to optimize the activity of effector T cells as well as alternate innate and adaptive immune effector cells. In this chapter, we discuss how T cell trafficking is blunted at the tumor blood vessel interface and how therapies that are effective in normalizing the tumor vasculature such as anti-VEGF, tyrosine kinase inhibitors and vaccines targeting tumor blood vessel-associated antigens, among others, can re-establish T cell infiltration into an inflammatory tumor microenvironment, leading to therapeutic benefits in the cancer setting.


Tumor vasculature Tumor microenvironment T cell trafficking Anti-angiogenic agents Immunotherapy 



α-Smooth muscle actin


A disintegrin and metalloproteinase


Adoptive cell transfer




Chimeric antigen receptor


Cytotoxic T lymphocyte


Cytotoxic T-lymphocyte-associated protein 4


Delta-like homologue 1


Dendritic cell




Endothelin B receptor


Extracellular matrix


Fibroblast growth factor


Food and Drug Administration


Human umbilical vein endothelial cells


Hypoxia inducible factor


Insulin-like growth factor


Intercellular adhesion molecule-1






Lymphocyte function-associated antigen-1


Major histocompatibility complex


Myeloid derived suppressor cell




Non-small cell lung cancer


Platelet-derived growth factor


Programmed cell death protein 1


Programmed cell death protein ligand 1


P-selectin glycoprotein ligand 1


Receptor-type tyrosine kinase


Regulator of G-protein signaling-5


Regulatory T cell


Renal cell carcinoma


Small cell lung cancer


T cell receptor


T helper type 1


Transforming growth factor


Tumor blood vessel-associated antigen


Tumor endothelial marker-1


Tumor infiltrating lymphocyte


Tumor microenvironment


Tumor necrosis factor-α


Tumor-associated macrophage


Tyrosine kinase inhibitors


Vascular adhesion molecule-1


Vascular endothelial cells


Vascular endothelial growth factor


VEGF receptor


Very late antigen-4



The authors would like to thank Dr. Ronald Fecek for reviewing this manuscript.

No potential conflicts of interest were disclosed.


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of ImmunologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Department of DermatologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.University of Pittsburgh Cancer InstitutePittsburghUSA

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