The Combination of Immune Checkpoint Blockade with Tumor Vessel Normalization as a Promising Therapeutic Strategy for Breast Cancer: An Overview of Preclinical and Clinical Studies

Abstract

Immune checkpoint inhibitors (ICIs) have a modest clinical activity when administered as monotherapy against breast cancer (BC), the most common malignancy in women. Novel combinatorial strategies are currently being investigated to overcome resistance to ICIs and promote antitumor immune responses in a greater proportion of BC patients. Recent studies have shown that the BC abnormal vasculature is associated with immune suppression in patients, and hampers both drug delivery and immune effector cell trafficking to tumor nests. Thus, strategies directed at normalizing (i.e., at remodeling and stabilizing) the immature, abnormal tumor vessels are receiving much attention. In particular, the combination of ICIs with tumor vessel normalizing agents is thought to hold great promise for the treatment of BC patients. Indeed, a compelling body of evidence indicates that the addition of low doses of antiangiogenic drugs to ICIs substantially improves antitumor immunity. In this review, we outline the impact that the reciprocal interactions occurring between tumor angiogenesis and immune cells have on the immune evasion and clinical progression of BC. In addition, we overview preclinical and clinical studies that are presently evaluating the therapeutic effectiveness of combining ICIs with antiangiogenic drugs in BC patients.

Preclinical multi‐physiologic monitoring of immediate‐early responses to diverse treatment strategies in breast cancer by optoacoustic imaging

“…At present, antiangiogenic therapy has been widely used as an effective approach to combat tumor angiogenesis. EVE acts as an mTOR inhibitor with antiangiogenic activity by reducing the production of hypoxia‐inducing factor 1α and vascular endothelial growth factor [30, 44]. In this study, the HbT signal in the EVE group was lower than that in the control group throughout the administration period.…”

“…Angiogenesis plays a crucial role in tumorigenesis and antiangiogenic therapy is still an important part of tumor therapy [30][31][32]. It is widely believed that during antiangiogenic therapy, there is a brief window of time for "vascular normalization," however, this time window is very short and unstable.…”

Genes ingenuity pathway analysis unveils smoothelin‐like 1 (SMTNL1) as a key regulatory protein involved in sodium pentobarbital‐induced growth inhibition in breast cancer

“…Multiple anti‐angiogenic agents have been used to treat TNBC, but limited efficacy is observed and the potential mechanisms are not completely understood 19 . Current evidence suggests that a vessel normalization strategy is beneficial to the treatment of breast cancer 20 . To restore the structure and function of tumor vasculature, vessel normalization promotes the perfusion of blood flow and decreases the hypoxia and acidosis in tumor tissues 21 .…”

“…19 Current evidence suggests that a vessel normalization strategy is beneficial to the treatment of breast cancer. 20 To restore the structure and function of tumor vasculature, vessel normalization promotes the perfusion of blood flow and decreases the hypoxia and acidosis in tumor tissues. 21 Multiple agents, especially antiangiogenic agents, could normalize the tumor vessels and improve the oxygenation and delivery of drugs or immune cells.…”

Disintegrin-like Protein Strategy to Inhibit Aggressive Triple-Negative Breast Cancer

“…Angiogenesis is a crucial process involved in various physiological and pathological events, including embryonic development, tumor growth, metastasis, and inflammatory disorders [1,2]. Tumors rely on angiogenesis to obtain oxygen and nutrients, enabling invasion and metastasis [3,4]. The process of angiogenesis encompasses several steps, such as breakdown of the basement membrane, migration and proliferation of endothelial cells, formation of lumens, connection of new blood vessels with existing circulation, and extensive remodeling of the extracellular matrix (ECM) [5,6].…”