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Remodeling of Metastatic Vasculature Reduces Lung Colonization and Sensitizes Overt Metastases to Immunotherapy.
- Source :
-
Cell reports [Cell Rep] 2020 Jan 21; Vol. 30 (3), pp. 714-724.e5. - Publication Year :
- 2020
-
Abstract
- 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 pre-metastatic 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 intra-metastatic blood vessels and increases GrzB <superscript>+</superscript> effector T cells. Successful treatment induces high endothelial venules (HEVs) and lymphocyte clusters, which sensitize refractory lung metastases to anti-PD-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.<br />Competing Interests: Declaration of Interests R.G. and A.J.-P. hold a patent related to this work.<br /> (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Humans
Immunity
Lung Neoplasms immunology
Lung Neoplasms pathology
Lung Neoplasms therapy
Lymph Nodes pathology
Male
Melanoma immunology
Melanoma pathology
Melanoma therapy
Mice, Inbred C57BL
Neoadjuvant Therapy
Neoplasm Metastasis
Peptides therapeutic use
Programmed Cell Death 1 Receptor immunology
T-Lymphocytes immunology
Tumor Necrosis Factor Ligand Superfamily Member 14 therapeutic use
Immunotherapy
Lung blood supply
Lung pathology
Neovascularization, Pathologic pathology
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 30
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 31968248
- Full Text :
- https://doi.org/10.1016/j.celrep.2019.12.013