Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity.
Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity.
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DOI：
10.1038/s12276-020-00500-y
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发表时间：
2020-09
影响因子：
12.8
通讯作者：
Kim C
中科院分区：
文献类型：
--
作者：
Lee WS;Yang H;Chon HJ;Kim C
使用免疫检查点抑制剂（ICIs）的癌症免疫治疗已经彻底改变了晚期癌症的治疗。然而，肿瘤微环境（TME）作为一个强大的屏障，严重损害了ICIs的疗效。虽然肿瘤血管和免疫细胞之间的串扰决定了抗肿瘤免疫的性质，但在肿瘤生长过程中，它倾向于破坏性循环。首先，混乱的肿瘤血管阻碍CD8+ T细胞运输到TME，使效应功能失效，甚至杀死T细胞。此外，作为血管生成的关键驱动因子，VEGF会干扰树突状细胞的成熟，从而抑制T细胞的启动，并且VEGF还会诱导toxo介导的CD8+ T细胞的衰竭。同时，多种先天性和适应性免疫细胞参与肿瘤血管的畸形。瘤原m2样巨噬细胞以及TH2和Treg细胞分泌促血管生成因子，加速不受控制的血管生成，促进血管不成熟。虽然CD8+ T和CD4+ TH1细胞通过分泌IFN-γ抑制血管生成并诱导血管成熟，但由于肿瘤血管畸形，它们无法浸润TME。这些发现导致临床前研究表明，同时靶向肿瘤血管和免疫是一种可行的策略，可以使异常的血管免疫串扰正常化，并增强癌症免疫治疗。此外，这种联合策略已经通过最近的关键临床试验得到了明显的证明，并获得了FDA的批准，现在正在用于肾癌、肝癌、肺癌或子宫癌患者。总之，结合抗血管生成治疗和ICI是一种有效的治疗策略，可以增强癌症免疫，并将进一步扩大癌症治疗的前景。结合抑制血管生长的抗血管生成药物和促进杀死癌症的免疫细胞激活的免疫检查点抑制剂，为癌症患者提供了一种有希望的新治疗方案。在一篇综述文章中，由韩国城南CHA大学医学院的Chan Kim和Hong Jae Chon领导的研究小组讨论了肿瘤微环境中血管和免疫细胞之间的分子串扰，这种生物学上的相互联系为双重治疗策略提供了令人信服的理由。研究人员总结了临床前和临床数据，证明了将免疫疗法与针对多种肿瘤类型的血管生长的治疗相结合的潜力。到目前为止，这些数据已经导致监管部门批准了肺癌、肾癌、肝癌和子宫内膜癌患者的治疗。
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. 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.
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