Angiogenic cancer blood vessels are highly chaotic and form a barrier which prevents the influx of anti-cancer immune cells. Re-education of the tumour microenvironment, including normalization of the tumour vasculature, is an emerging concept shown to improve anti-cancer immunotherapy. Taking vessel normalization one step further, we develop reagents with the dual capacity to modulate the angiogenic tumour vasculature and induce intratumoral tertiary lymphoid structures (TLS). Intratumoral TLS which arise on a background of normalized blood vessels trigger influx of endogenous immune cells into primary tumours that are resistant to any form of immunotherapy.
In contrast to primary tumours, very little is known about the vascularization process and immune landscape during metastatic progression. Vascular hyperpermeability is one of the earliest events during formation of a pre-metastatic niche at distant sites. Our recent data demonstrate that our reagent, referred to as LIGHT (or TNFSF14)-VTP (vascular targeting peptide), reverses vascular hyperpermeability, fibronectin deposition and extravasation of tumour cells in pre-metastatic lungs. This translates into significantly reduced outgrowth of lung micrometastases in an adjuvant setting after resection of the primary tumour. Moreover, following LIGHT-VTP therapy, non-inflamed overt lung metastases become responsive to anti-PD-1 antibodies resulting in sustained intra-lesional inflammation on a background of normalized vessels and TLS. Since surgical tumour removal is rarely curative in advanced cancers, and treatment options for metastases are limited, LIGHT-VTP combination immunotherapies are of high translational relevance.