Remodeling of Metastatic Vasculature Reduces Lung Colonization and Sensitizes Overt Metastases to Immunotherapy

Abstract

Summary: 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+ 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. : Treatment options for metastatic cancer are limited. He et al. develop a cytokine therapy that specifically targets leaky blood vessels in the pre-metastatic niche and established lung metastases. Treatment repairs vessel leakiness, prevents outgrowth of circulating cancer cells, and also sensitizes already established lung metastases for checkpoint inhibition. Keywords: metastasis, angiogenesis, vessel normalization, tertiary lymph node structures, immunotherapy, high endothelial venules, pre-metastatic niche, peptide tumor targeting