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

Abstract

Highlights d Vascular LIGHT targeting in tumors prevents cancer cell intravasation d Restored vascular integrity in the pre-metastatic niche reduces extravasation d LIGHT-VTP normalizes blood vessels in overt metastatic lesions d LIGHT-VTP sensitizes refractory lung metastasis to checkpoint inhibition

A LIGHTning Strike to the Metastatic Niche

“…VTP, also known as ''CGKRK'' owing to its amino acid sequence, was shown previously to bind heparan sulfates on angiogenic blood vessels in mouse tumor models (Hoffman et al, 2003). Now, He et al (2019) demonstrate that VTP also recognizes the vasculature of lungs that have been exposed to tumor-derived signals. Although the mode whereby VTP targets lung blood vessels of tumor-bearing mice remains unknown, it is possible that tumor-induced vascular hyperpermeability facilitated diffusion of LIGHT, while perivascular accumulation of extracellular matrix contributed to an increase in its binding and retention.…”

“…Tumors may also alter the properties of normal blood vessels in pre-metastatic niches-sites where cancer cells that disseminate from a primary tumor begin the colonization of a distant organ (Peinado et al, 2017). Writing in Cell Reports, He et al (2019) show that reversing tumor-induced vascular abnormalities in pre-metastatic sites or early-established metastases limits lung colonization by the tumor and enhances the efficacy of immune checkpoint blockade, a clinically approved immunotherapy ( Figure 1).…”

“…In the new study, He et al (2019) examined the pulmonary blood vessels of mice carrying subcutaneously growing tumors. They found that the tumors had remotely altered the lung blood vessels, which became leakier and displayed abundant deposition of extracellular matrix.…”

“…The VTP peptide efficiently recognized the pulmonary vasculature of tumorbearing mice but had little affinity for that of naive mice (He et al, 2019). VTP, also known as ''CGKRK'' owing to its amino acid sequence, was shown previously to bind heparan sulfates on angiogenic blood vessels in mouse tumor models (Hoffman et al, 2003).…”

“…Can LIGHT-VTP also impair the growth of pre-established metastases? To address this question, He et al (2019) employed a model in which lung tumors are established in mice through the intravenous injection of cancer cells. Although this model does not fully recapitulate the natural history of bona fide metastases, it can approximate metastatic lung disease in preclinical trials.…”