A Window of Opportunity: Targeting Cancer Endothelium to Enhance Immunotherapy

Abstract

Vascular abnormalities in tumors have a major impact on the immune microenvironment in tumors. The consequences of abnormal vasculature include increased hypoxia, acidosis, high intra-tumoral fluid pressure, and angiogenesis. This introduces an immunosuppressive microenvironment that alters immune cell maturation, activation, and trafficking, which supports tumor immune evasion and dissemination of tumor cells. Increasing data suggests that cancer endothelium is a major barrier for traveling leukocytes, ranging from a partial blockade resulting in a selective endothelial barrier, to a complete immune infiltration blockade associated with immune exclusion and immune desert cancer phenotypes. Failed immune cell trafficking as well as immunosuppression within the tumor microenvironment limits the efficacy of immunotherapeutic approaches. As such, targeting proteins with key roles in angiogenesis may potentially reduce immunosuppression and might restore infiltration of anti-tumor immune cells, creating a therapeutic window for successful immunotherapy. In this review, we provide a comprehensive overview of established as well as more controversial endothelial pathways that govern selective immune cell trafficking across cancer endothelium. Additionally, we discuss recent insights and strategies that target tumor vasculature in order to increase infiltration of cytotoxic immune cells during the therapeutic window of vascular normalization hereby improving the efficacy of immunotherapy.

Melanoma Associated Chitinase 3-Like 1 Promoted Endothelial Cell Activation and Immune Cell Recruitment

“…To better understand the biological relevance of the competitive replacement of HS or matrix-bound factors by CHI3L1 we focused in our experiments on endothelial cell activation. Within the tumor tissue, the endothelium can be considered a gatekeeper that regulates the infiltration of immune cells and consequently the efficiency of immunotherapy [ 34 , 35 ]. To our knowledge, there are no clinical data available analyzing CHI3L1 in the context of current state-of-the-art immunotherapies applying CTLA-4 or PD-1 inhibition in melanoma.…”

Therapeutic Targeting of the Tumor Microenvironment

“…Bevacizumab, a humanized anti-VEGFA mAb, was the first approved antiangiogenic agent for several cancers, including metastatic colorectal cancer, cervical cancer, NSCLC, glioblastoma, and metastatic renal cell cancer (www.accessdata.fda.gov). Most of the ongoing trials are currently focused on assessing the combination of anti-VEGF therapy with chemotherapeutic agents (215) or immunotherapies (216,217). A meta-analysis of randomized control trials comparing the effect of different chemotherapeutic drugs alone, or in combination with bevacizumab, in metastatic colorectal cancer showed a beneficial effect of the combination in extending OS, PFS, and ORR (218).…”

Alternative Vascularization Mechanisms in Tumor Resistance to Therapy

“…In addition, vessels and molecular effectors of tumor vessel development can modulate cell responses to therapies through regulation of the metabolic and physical properties of the local environment. For example, hypoxia, acidosis, and high interstitial pressure deriving from vascular alterations lead to an immunosuppressive microenvironment that limits the efficacy of immunotherapy [ 7 ]. Finally, endothelial cells directly control chemosensitivity, through the release of angiocrine factors [ 8 ], contributing to tumor sensitivity or innate, intrinsic drug resistance.…”