The bidirectional link between tumor angiogenesis and immunity

Scriptie/masterproef: Doctoral Thesis

Uittreksel

Melanoma brain metastases are associated with a poor prognosis and are characterized by excessive neo-angiogenesis, which frequently leads to intracranial hemorrhage. The dominant regulator of angiogenesis is the Vascular Endothelial Growth Factor (VEGF) and its main receptor VEGF receptor 2 (VEGFR-2). Tumor cells secrete high amounts of VEGF, which
leads to uncontrolled formation of immature blood vessels. Besides its role in tumor angiogenesis, VEGF also has a strong immunosuppressive effect. Thus, targeting the VEGF-VEGFR pathway has become an important antitumoral strategy. Recently, immunotherapy has shown to increase the overall survival of patients with metastatic melanoma. However, in
patients with melanoma brain metastases immunotherapy has limited activity due to the natural immunosuppressive environment present in the brain. We investigated whether axitinib, a tyrosine kinase inhibitor against VEGFR-1, -2 and 3, can enhance the antitumor immune response in monotherapy or when combined with immunotherapy. Firstly, we showed
that axitinib reduces tumor growth and increases survival through reduction of the immunosuppressive microenvironment in subcutaneous and intracranial mouse melanoma models. Secondly, when axitinib was combined with immunotherapy we observed a stronger reduction of tumor growth and an increased antitumor immune response. Thirdly, we demonstrate that axitinib has beneficial effects on the immune system of recurrent glioblastoma patients, however patients with progressive disease displayed an enhanced preexisting immunosuppression. In conclusion, we showed that combining antiangiogenesis with immunotherapy has beneficial effects on the antitumor immune response
Datum Prijs27 jan 2016
TaalEnglish
Toekennende instantie
  • Vrije Universiteit Brussel
BegeleiderJoeri Aerts (Promotor), Kris Thielemans (Co-promotor), Bart Neyns (Co-promotor), Jacques De Keyser (Jury), Mark De Ridder (Jury), Geert Raes (Jury), Olivier Chinot (Jury), Olivier De Witte (Jury) & Sandra Liekens (Jury)

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