The tumour microenvironment confers profound resistance to anti-cancer therapies in no small part due to impaired perfusion, limited drug access and homing of cytotoxic T cells to the tumour site. Re-education of the tumour microenvironment, including normalization of the tumour vasculature, is an emerging concept shown to improve anti-cancer therapy. There are currently no clinical interventions which effect long-lasting normalization.
By targeting the TNF superfamily member LIGHT to tumour vessels, we have developed a reagent, referred to as LIGHT-VTP (VTP: vascular targeting peptide), with unprecedented dual capacity to modulate the angiogenic tumour vasculature and induce intratumoral tertiary lymphoid structures (TLS).
Normalization occurs by induced expression of contractile markers in intratumoral pericytes which in turn re-establishes tight pericyte-vessel alignment (1). Restoring vessel integrity improves tumur perfusion and acts as adjuvant to chemo- and immunotherapy. Moreover, enhanced pericyte contractility and tighter blood vessels prevent metastatic tumour spreading.
TLS on a background of normalized blood vessels trigger influx of endogenous T cells into autochthonous and orthotopic tumours which are resistant to any form of immunotherapy such as pancreatic tumours and glioblastoma. In combination with checkpoint inhibition, intratumoral priming sites and high numbers of cytotoxic effector T cells are generated with ensuing survival benefits (2). Vessel normalization and TLS induction can be reproduced by adoptive transfer of LIGHT-stimulated macrophages alone demonstrating the central role of peri-vascular macrophages and their re-education during LIGHT-VTP therapy.
Vascular targeting peptides strongly bind to blood vessels in freshly resected human pancreatic and primary brain cancers thus demonstrating the translational potential of peptide-mediated LIGHT therapy.