Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?

Abstract

Angiogenesis is defined as the formation of new blood vessels from preexisting vessels and has been characterized as an essential process for tumor cell proliferation and viability. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve tumor of nutrients and oxygen, primarily through blockade of VEGF/VEGFR signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, alone or in combination with chemotherapy or other targeted therapies. But this success had only limited impact on overall survival of cancer patients and rarely resulted in durable responses. Given the recent success of immunotherapies, combinations of anti-angiogenics with immune checkpoint blockers have become an attractive strategy. However, implementing such combinations will require a better mechanistic understanding of their interaction. Due to overexpression of pro-angiogenic factors in tumors, their vasculature is often tortuous and disorganized, with excessively branched leaky vessels. This enhances vascular permeability, which in turn is associated with high interstitial fluid pressure, and a reduction in blood perfusion and oxygenation. Judicious dosing of anti-angiogenic treatment can transiently normalize the tumor vasculature by decreasing vascular permeability and improving tumor perfusion and blood flow, and synergize with immunotherapy in this time window. However, anti-angiogenics may also excessively prune tumor vessels in a dose and time-dependent manner, which induces hypoxia and immunosuppression, including increased expression of the immune checkpoint programmed death receptor ligand (PD-L1). This review focuses on revisiting the concept of anti-angiogenesis in combination with immunotherapy as a strategy for cancer treatment.

Keywords: Antiangiogenesis; Hypoxia; Immunotherapy; Normalization; PD-1; VEGF.

Conflict of interest statement

Conflicts of interest: DGD receives research funding from Merrimack, Leap Tx, Bristol-Meyers-Squibb and Bayer.

Figures

Figure 1. Potential Effects of Antiangiogenic Therapy on Tumor Vascular Function and Impact on Anti-tumor Immunity

Blood vasculature is normal tissues is maintained by a balanced expression of pro- and anti-angiogenic molecules, which ensures a normal structure and function (blood flow, left). The normal architecture and function is lost in cancer, due to abnormal expression of pro-angiogenic factors by malignant and stromal cells. This leads to inefficient blood perfusion, hypoxia, and an immunosuppressive tumor microenvironment (TME). This is characterized by increased infiltration by T regulatory cells (Tregs), myeloid suppressor cells (MDSCs), and pro-tumor (M2-type) tumor-associated macrophages (TAMs), and reduced infiltration by cytotoxic T cells (CTLs) and mature dendritic cells (DCs)/antigen presenting cells. Antiangiogenic therapy may have different effects on tumor vasculature, depending on the dose, timing and type of antiangiogenic agent. Treatment may result in: 1) a transiently normalized vasculature, which leads to reductions in hypoxia and reprogramming of the immune TME toward an immunosupportive one, with predominance of anti-tumor (M1-type) TAMs, CTLs and mature DCs, 2) no change, or 3) excessive pruning of the vasculature, with further decreases in blood flow and increases in hypoxia. These effects may be critically important for combination of antiangiogenics with immunotherapies (See Ref. 200). Illustration courtesy of Dr. Lance L. Munn (MGH Boston).