Journal
CELL REPORTS
Volume 30, Issue 3, Pages 714-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.12.013
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Funding
- National Health and Medical Research Council of Australia [APP1122108, APP1141849, APP1058073]
- Cancer Council Western Australia [APP1098579]
- Cancer Council Western Australia (Suzanne Cavanagh Early Career Funding)
- Cancer Council Western Australia (Vacation Research Scholarship)
- Cancer Research Institute Clinic and Laboratory Integration Program (CLIP) grant
- Tour de Cure Senior Research Grant
- Woodside Energy Fellowship
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Due to limited current therapies, metastases are the primary cause of mortality in cancer patients. Here, we employ a fusion compound of the cytokine LIGHT and a vascular targeting peptide (LIGHT-VTP) that homes to angiogenic blood vessels in primary tumors. We show in primary mouse lung cancer that normalization of tumor vasculature by LIGHT-VTP prevents cancer cell intravasation. Further, LIGHT-VTP efficiently targets pathological blood vessels in the premetastatic niche, reducing vascular hyper-permeability and extracellular matrix (ECM) deposition, thus blocking metastatic lung colonization. Moreover, we demonstrate that mouse and human metastatic melanoma deposits are targetable by VTP. In overt melanoma metastases, LIGHT-VTP normalizes intrametastatic blood vessels and increases GrzB(+) effector T cells. Successful treatment induces high endothelial venules (HEVs) and lymphocyte clusters, which sensitize refractory lung metastases to antiPD-1 checkpoint inhibitors. These findings demonstrate an important application for LIGHT-VTP therapy in preventing metastatic development as well as exerting anti-tumor effects in established metastases.
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