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

Experimental & Molecular Medicine 2020년 52권 9호 p.11 ~ 11
이원석, 양한나, 전홍재, Kim Chan,
소속 상세정보
이원석 ( Lee Won-Suk ) - CHA University School of Medicine CHA Bundang Medical Center Department of Medical Oncology
양한나 ( Yang Han-Nah ) - CHA University School of Medicine CHA Bundang Medical Center Department of Medical Oncology
전홍재 ( Chon Hong-Jae ) - CHA University School of Medicine CHA Bundang Medical Center Department of Medical Oncology
 ( Kim Chan ) - CHA University School of Medicine CHA Bundang Medical Center Department of Medical Oncology

Abstract


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 TH2 and Treg cells secrete pro-angiogenic factors that accelerate uncontrolled angiogenesis and promote vascular immaturity. While CD8+ T and CD4+ TH1 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.

키워드

Cancer immunotherapy; Cancer microenvironment; Targeted therapies; Tumour angiogenesis; Tumour immunology

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