Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity

• Published in: Experimental & molecular medicine Vol. 52; no. 9; pp. 1475 - 1485
• Main Authors: Lee, Won Suk, Yang, Hannah, Chon, Hong Jae, Kim, Chan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2020; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13/1; 13/21; 13/31; 13/51; 631/67/327; 64/110; 64/60; 692/699/67/1059/2325; 692/699/67/1059/602; 692/699/67/2328; 692/699/67/580; Angiogenesis; Angiogenesis Inhibitors - administration & dosage; Animals; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomedical and Life Sciences; Biomedicine; Blood vessels; Cancer; Cancer immunotherapy; CD4 antigen; CD8 antigen; Cell activation; Cell Communication - genetics; Cell Communication - immunology; Clinical trials; Dendritic cells; Endometrium; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - administration & dosage; Immunity (Disease); Immunomodulation - drug effects; Immunosuppressive agents; Immunotherapy; Kidneys; Liver cancer; Lung cancer; Lymphocytes T; Macrophages; Medical Biochemistry; Molecular Medicine; Molecular Targeted Therapy; Neoplasms - drug therapy; Neoplasms - etiology; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - immunology; Neovascularization, Pathologic - metabolism; Patients; Review; Review Article; Signal Transduction; Stem Cells; Treatment Outcome; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Tumors; Uterine cancer; Vascular endothelial growth factor; γ-Interferon; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/s12276-020-00500-y

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced cancers. However, the tumor microenvironment (TME) functions as a formidable barrier that severely impairs the efficacy of ICIs. While the crosstalk between tumor vessels and immune cells determines the nature of anti-tumor immunity, it is skewed toward a destructive cycle in growing tumors. First, the disorganized tumor vessels hinder CD8 + T cell trafficking into the TME, disable effector functions, and even kill T cells. Moreover, VEGF, the key driver of angiogenesis, interferes with the maturation of dendritic cells, thereby suppressing T cell priming, and VEGF also induces TOX-mediated exhaustion of CD8 + T cells. Meanwhile, a variety of innate and adaptive immune cells contribute to the malformation of tumor vessels. Protumoral M2-like macrophages as well as T H 2 and Treg cells secrete pro-angiogenic factors that accelerate uncontrolled angiogenesis and promote vascular immaturity. While CD8 + T and CD4 + T H 1 cells suppress angiogenesis and induce vascular maturation by secreting IFN-γ, they are unable to infiltrate the TME due to malformed tumor vessels. These findings led to preclinical studies that demonstrated that simultaneous targeting of tumor vessels and immunity is a viable strategy to normalize aberrant vascular-immune crosstalk and potentiate cancer immunotherapy. Furthermore, this combination strategy has been evidently demonstrated through recent pivotal clinical trials, granted approval from FDA, and is now being used in patients with kidney, liver, lung, or uterine cancer. Overall, combining anti-angiogenic therapy and ICI is a valid therapeutic strategy that can enhance cancer immunity and will further expand the landscape of cancer treatment. Cancer: Combination treatment targeting tumor blood vessels and immunity Combining anti-angiogenesis drugs that reduce the growth of blood vessels and immune checkpoint inhibitors that promote the activation of cancer-killing immune cells offers a promising new therapeutic regimen for patients with cancer. In a review article, a team led by Chan Kim and Hong Jae Chon from the CHA University School of Medicine in Seongnam, South Korea, discuss the molecular crosstalk between blood vessels and immune cells in the tumor microenvironment, a biological interconnectedness that provides a compelling rationale for the dual treatment strategy. The researchers summarize preclinical and clinical data demonstrating the potential of combining immunotherapy with treatment targeting blood vessel growth across a range of tumor types. These data have so far led to regulatory approvals for patients with cancers of the lung, kidney, liver and endometrium.