Modulation of the Vascular-Immune Environment in Metastatic Cancer

SIMPLE SUMMARY: Abnormal blood vessels restrict immune cell access into primary cancers and thus contribute to resistance to immunotherapy. In contrast, vessel remodeling or normalization strategies increase anti-cancer immune responses. Much less is known about the inter-relationship of blood vessels and immune cells at secondary metastatic sites. This review specifically explores how abnormal vascular features in the pre-metastatic niche can be targeted and potentially repaired. Moreover, the growth of established metastases relies on blood supply from both pre-existing, co-opted and newly formed angiogenic vessels. The co-existence of blood vessels with different maturation status may impact on vascular targeting strategies and responsiveness to immunotherapy, thus requiring innovative approaches to treat advanced 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.