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Vascular Normalization, T Cell Trafficking and Anti-tumor Immunity

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

Abstract

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.

Keywords

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

Abbreviations

αSMA

α-Smooth muscle actin

ADAM

A disintegrin and metalloproteinase

ACT

Adoptive cell transfer

Ang

Angiopoietin

CAR

Chimeric antigen receptor

CTL

Cytotoxic T lymphocyte

CTLA-4

Cytotoxic T-lymphocyte-associated protein 4

DLK1

Delta-like homologue 1

DC

Dendritic cell

ET

Endothelin

ETBR

Endothelin B receptor

ECM

Extracellular matrix

FGF

Fibroblast growth factor

FDA

Food and Drug Administration

HUVEC

Human umbilical vein endothelial cells

HIF

Hypoxia inducible factor

IGF

Insulin-like growth factor

ICAM-1

Intercellular adhesion molecule-1

IFNγ

Interferon-γ

IL

Interleukin

LFA-1

Lymphocyte function-associated antigen-1

MHC

Major histocompatibility complex

MDSC

Myeloid derived suppressor cell

NRP

Neuropilin

NSCLC

Non-small cell lung cancer

PDGF

Platelet-derived growth factor

PD-1

Programmed cell death protein 1

PD-L1

Programmed cell death protein ligand 1

PSGL-1

P-selectin glycoprotein ligand 1

RTK

Receptor-type tyrosine kinase

RGS-5

Regulator of G-protein signaling-5

Treg

Regulatory T cell

RCC

Renal cell carcinoma

SCLC

Small cell lung cancer

TCR

T cell receptor

Th1

T helper type 1

TGF

Transforming growth factor

TBVA

Tumor blood vessel-associated antigen

TEM1

Tumor endothelial marker-1

TIL

Tumor infiltrating lymphocyte

TME

Tumor microenvironment

TNFα

Tumor necrosis factor-α

TAM

Tumor-associated macrophage

TKI

Tyrosine kinase inhibitors

VCAM-1

Vascular adhesion molecule-1

VEC

Vascular endothelial cells

VEGF

Vascular endothelial growth factor

VEGFR

VEGF receptor

VLA-4

Very late antigen-4

Notes

Acknowledgments

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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