Modulation of the Vascular-Immune Environment in Metastatic Cancer

Abstract

Advanced metastatic cancer is rarely curable. While immunotherapy has changed the oncological landscape profoundly, cure in metastatic disease remains the exception. Tumor blood vessels are crucial regulators of tumor perfusion, immune cell influx and metastatic dissemination. Indeed, vascular hyperpermeability is a key feature of primary tumors, the pre-metastatic niche in host tissue and overt metastases at secondary sites. Combining anti-angiogenesis and immune therapies may therefore unlock synergistic effects by inducing a stabilized vascular network permissive for effector T cell trafficking and function. However, anti-angiogenesis therapies, as currently applied, are hampered by intrinsic or adaptive resistance mechanisms at primary and distant tumor sites. In particular, heterogeneous vascular and immune environments which can arise in metastatic lesions of the same individual pose significant challenges for currently approved drugs. Thus, more consideration needs to be given to tailoring new combinations of vascular and immunotherapies, including dosage and timing regimens to specific disease microenvironments.

Keywords: angiogenesis; immunotherapy; metastasis; tertiary lymphoid structures; vessel co-option; vessel normalization.

Figure 1

LIGHT-VTP therapy has distinct intra-tumoral effects at different stages during metastatic progression. Left, LIGHT-VTP therapy normalizes primary tumor vessels and improves vessel integrity and tumor perfusion, which also limits tumor cell intravasation into the circulation (30); arrows indicate well perfused vessels in yellow (overlay of CD31⁺ blood vessels (red) with i.v.-injected FITC-lectin (green) as surrogate marker for perfusion). Middle, LIGHT-VTP therapy reverses the hyperpermeability of pre-metastatic lung vessels (green) as measured by extravasated high molecular dextran (red). Arrow heads illustrate hyperpermeable areas in tumor-conditioned, untreated lung. In correlation with reduction of hyperpermeability, LIGHT-VTP treatment also reduces ECM (fibronectin) deposition and extravasation of circulating tumor cells (30). Right, in overt metastases, LIGHT-VTP therapy normalizes blood vessels, induces HEVs and small immature T and B cell clusters. LIGHT-VTP sensitizes to anti-PD-1 checkpoint inhibition and double treatment induces mature TLS with distinct T cell (red) and B cell (green) zones, and HEVs (white). Scale bars, 50 µm.

Figure 2

Combination Vascular-Immune Therapy in Metastatic Cancer. Left, depicted are 2 distinct metastatic vascularization patterns in host tissue, neo-angiogenesis and co-option of existing blood vessels. Developing tumors are devoid of lymphocytes and therefore immune ‘cold’. Middle, vascular remodeling therapy, e.g., anti-angiogenesis and anti-co-option strategies, normalize aberrant angiogenic vessels and reduce cancer adhesion to pre-existing vessels. Improved tumor perfusion facilitates lymphocyte influx and alleviates immune suppression, thus creating an immune ‘intermediate’ environment. Right, this sets the stage for checkpoint inhibitors to activate local adaptive immunity and generate a positive feedback loop where normalized vessels increase T cell infiltration and activated effector T cells normalize blood vessels for more lymphocyte influx. A critical mass of T and B cells forms clusters resembling tertiary lymphoid structures (TLS) containing high endothelial venules (HEVs) which further support naive and memory T cell migration. A self-perpetuating immune ‘hot’ environment has been created following sequential vascular remodeling and immune enhancing combination therapies.