Explore VEGF

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  • Pathway Overview
  • Role In Cancer
  • Targeting VEGF
  • Potential of Combinations
Pathway Overview

The VEGF pathway is a potent inducer of angiogenesis1

VEGF (vascular endothelial growth factor) is a multifunctional cytokine and member of the PDGF (platelet-derived growth factor) superfamily, which stimulates vascular endothelial cell growth, survival, and proliferation.1-3

angiogenesis
Cells secrete VEGF to stimulate vasculogenesis and angiogenesis3

VEGF promotes blood vessel formation by4

  • Increasing microvascular cellular permeability to plasma proteins
  • Inducing endothelial cell division and migration
  • Reversing senescence
  • Protecting endothelial cells from apoptosis
VEGF plays a key role in several normal physiological functions5

VEGF is integral for stimulating blood vessel growth in utero, after physical activity or injury, or to bypass haematologic blockages.5

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Role In Cancer

VEGF overexpression promotes angiogenesis and disrupts the cancer immunity cycle1,6,7

VEGF can play a central role in tumour development, providing the blood supply needed to drive tumour growth and metastasis.2

  • VEGF is overexpressed in most solid cancers and lymphomas, including lung cancer and renal cell carcinoma
  • Elevated VEGF levels are associated with poor clinical outcomes in numerous tumour types

In addition to its angiogenic effects, VEGF overexpression helps tumors evade the antitumor immune response by disrupting multiple steps in the cancer immunity cycle1,6,7

VEGF inhibits dendritic cell maturation

VEGF inhibits dendritic cell maturation by limiting the activation of specific pathways in immature dendritic cells

  • This prevents the functional maturation of dendritic cells, and may result in inefficient priming and activation of T cells
VEGF can disrupt T-cell infiltration into the tumour6,7

VEGF expression can downregulate cell adhesion molecules on endothelial cells4,6,8

  • This limits T-cell adhesion to the endothelium, thwarting infiltration of T cells into the tumour microenvironment

VEGF-mediated angiogenesis also leads to dysfunctional vasculature that acts as a structural inhibitor of T-cell infiltration.9

VEGF angiogenesis
 
VEGF promotes an immunosuppressive tumour microenvironment6,10

VEGF further promotes an immunosuppressive tumour microenvironment by inducing myeloid-derived suppressor cell accumulation and regulatory T-cell proliferation.6,10

  • This in turn prevents activation and proliferation of cytotoxic T-cells in the tumour microenvironment and subsequent recognition of cancer cells by T cells
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Targeting VEGF

VEGF inhibition may address these mechanisms of immune escape

VEGF inhibition is a well-established approach to promoting vascular normalisation in tumours that overexpress VEGF. Additionally, targeting VEGF can help restore the cancer immunity cycle in multiple ways.6,11,12  

VEGF inhibition drives dendritic cell maturation

VEGF inhibition can drive dendritic cell maturation, promoting the recognition of neoantigens and subsequent priming and activation of T Cells.

VEGF inhibition increases T-cell infiltration into the tumour microenvironment6,12,13

Inhibiting the VEGF pathway can lead to both vascular normalisation and increased expression of cell adhesion molecules on endothelial cells, resulting in CD8+ T-cell infiltration.6

T cell
Tumour cells
VEGF inhibition
T-cell infiltration
 
 

VEGF inhibition decreases the presence of immunosuppressive immune cells in the tumour microenvironment10

VEGF pathway inhibition can decrease the presence of myeloid-derived suppressor cells and regulatory T cells, further promoting antitumour immune activity.10

Collectively, VEGF inhibition may play a role in reprogramming the tumour milieu from an immunosuppressive to an immune permissive microenvironment.10

 
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Potential of Combinations

Targeting VEGF together with PD-L1 may have a synergistic effect on restoring cancer immunity7,11

Tumours can employ multiple mechanisms to evade the immune response, requiring a strategy that involves a combination of targets to improve therapeutic outcomes.11

Combining inhibition of the VEGF and PD-L1 pathways may have a synergistic effect on invigorating T-cell activity against tumour cells.7,11

  • The effects of VEGF inhibition can create an immune permissive and inflamed tumour microenvironment, and can lead to upregulation of PD-L112
  • Targeting PD-L1 simultaneously can prevent T-cell deactivation, which results in tumour cell killing11,14
  • Inhibiting both VEGF and PD-L1 increased intratumoural CD8+ T-cell infiltration and reduced tumour size in an early-phase study of renal cell carcinoma (RCC)13
 
 
 
 
 
 

Roche is actively investigating the synergistic potential of targeting both the VEGF and PD-L1 pathways in several tumour types, including lung cancer, renal cell carcinoma, and hepatocellular carcinoma

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References 
  1. Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 1995;146:1029-1039. PMID: 7538264
  2. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011-1027. PMID: 15585754
  3. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor—targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23:1028-1043. PMID: 15534359
  4. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002;20:4368-4380. PMID: 12409337
  5. Maharaj ASR, D’Amore PA. Roles for VEGF in adults. Microvasc Res. 2007;74:110-113. PMID: 17532010
  6. Terme M, Colussi O, Marcheteau E, Tanchot C, Tartour E, Taieb J. Modulation of immunity by antiangiogenic molecules in cancer. Clin Dev Immunol. 2012;2012:492920. doi:10.1155/2012/492920. PMID: 23320019
  7. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27:1492-1504. PMID: 27207108
  8. Jacobsen J, Grankvist K, Rasmuson T, Bergh A, Landberg G, Ljungberg B. Expression of vascular endothelial growth factor protein in human renal cell carcinoma. BJU Int. 2004;93:297-302. PMID: 14764126
  9. Turley SJ, Cremasco V, Astarita JL. Immunological hallmarks of stromal cells in the tumor microenvironment. Nat Rev Immunol. 2015;15(11):669-682. PMID: 26471778
  10. Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015;212:139-148. PMID: 25601652
  11. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321-330. PMID: 28102259
  12. Liu XD, Hoang A, Zhou L, et al. Resistance to antiangiogenic therapy is associated with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma. Cancer Immunol Res. 2015;3:1017-1029. PMID: 26014097
  13. J.J. Wallin, J.C. Bendell, R. Funke, et. al. Nature Communications 7 (2016) 12624. PMID: 27571927​
  14. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. PMID: 23890059

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