The Combination of Immune Checkpoint Blockade and Angiogenesis Inhibitors in the Treatment of Advanced Non-Small Cell Lung Cancer

Abstract

Immune checkpoint blockade (ICB) has become a standard treatment for non-small cell lung cancer (NSCLC). However, most patients with NSCLC do not benefit from these treatments. Abnormal vasculature is a hallmark of solid tumors and is involved in tumor immune escape. These abnormalities stem from the increase in the expression of pro-angiogenic factors, which is involved in the regulation of the function and migration of immune cells. Anti-angiogenic agents can normalize blood vessels, and thus transforming the tumor microenvironment from immunosuppressive to immune-supportive by increasing the infiltration and activation of immune cells. Therefore, the combination of immunotherapy with anti-angiogenesis is a promising strategy for cancer treatment. Here, we outline the current understanding of the mechanisms of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) signaling in tumor immune escape and progression, and summarize the preclinical studies and current clinical data of the combination of ICB and anti-angiogenic drugs in the treatment of advanced NSCLC.

Keywords: NSCLC; angiogenesis inhibitors; combination therapy; immune checkpoint blockade; immunotherapy; tumor microenvironment.

Figure 1

Monoclonal antibodies and small molecules targeting VEGF/VEGFR signaling in tumor angiogenesis. Monoclonal antibodies and small molecule TKIs targeting the VEGFA/VEGFR-2/PLCγ/Raf/PI3K signaling pathway could inhibit tumor angiogenesis and improve the efficiency of anticancer treatments. VEGF, Vascular Endothelial Growth Factor; VEGFR, Vascular Endothelial Growth Factor Receptor; TKI, Tyrosine Kinase Inhibitor; PI3K, Phosphoitide 3-Kinase; AKT, serine/threonine-specific protein kinase; mTOR, mammalian target of rapamycin; PLCγ, Phospholipase C γ; PI3P, Phosphatidylinositol 3-Phosphate; IP3, Inositol Triphosphate; DAG, Diacyl Glycerol; pKC, Protein Kinase C; MEK, Mitogen-activated protein kinase; MAPK, Mitogen Activated Protein Kinase.

Figure 2

VEGF and ANG2 regulate immune cells in tumor. The VEGF family can suppress the maturation, differentiation, and antigen presentation of APCs, DCs, NKs, and T cells, while both VEGF and Ang2 can improve the suppressive effect of Tregs, TAMs, and MDSCs. VEGF, Vascular Endothelial Growth Factor; ANG2, Angiogenin 2; APCs, Antigen Presenting Cells, DCs, Dendritic Cells; Treg, Regulatory T cells; NKs, Natural Killer Cells; TAMs, Tumor Associated Macrophages; MDSCs, Myeloid Derived Suppressor Cells.