Cell Death Research & Therapy (CDRT) Laboratory, Department for Cellular and Molecular Medicine, KU Leuven University of Leuven, Leuven, Belgium.
Cell Death Dis. 2018 Jan 25;9(2):115. doi: 10.1038/s41419-017-0061-0.
It is now well established that cancer cells co-exist within a complex environment with stromal cells and depend for their growth and dissemination on tight and plastic interactions with components of the tumor microenvironment (TME). Cancer cells incite the formation of new blood and lymphatic vessels from preexisting vessels to cope with their high nutrient/oxygen demand and favor tumor outgrowth. Research over the past decades has highlighted the crucial role played by tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T-cell-mediated immunosurveillance, which are the main hallmarks of cancers. The structurally and functionally aberrant tumor vasculature contributes to the protumorigenic and immunosuppressive TME by maintaining a cancer cell's permissive environment characterized by hypoxia, acidosis, and high interstitial pressure, while simultaneously generating a physical barrier to T cells' infiltration. Recent research moreover has shown that blood endothelial cells forming the tumor vessels can actively suppress the recruitment, adhesion, and activity of T cells. Likewise, during tumorigenesis the lymphatic vasculature undergoes dramatic remodeling that facilitates metastatic spreading of cancer cells and immunosuppression. Beyond carcinogenesis, the erratic tumor vasculature has been recently implicated in mechanisms of therapy resistance, including those limiting the efficacy of clinically approved immunotherapies, such as immune checkpoint blockers and adoptive T-cell transfer. In this review, we discuss emerging evidence highlighting the major role played by tumor-associated blood and lymphatic vasculature in thwarting immunosurveillance mechanisms and antitumor immunity. Moreover, we also discuss novel therapeutic approaches targeting the tumor vasculature and their potential to help overcoming immunotherapy resistance.
现在已经充分证实，癌细胞与基质细胞共存于一个复杂的环境中，其生长和扩散依赖于与肿瘤微环境（TME）成分的紧密和灵活的相互作用。癌细胞促使新的血管和淋巴管从现有血管中形成，以满足其高营养/氧气需求，并促进肿瘤生长。过去几十年来的研究强调了肿瘤相关的血液和淋巴管在支持免疫逃逸和颠覆 T 细胞介导的免疫监视方面所起的关键作用，这是癌症的主要特征。结构和功能异常的肿瘤血管通过维持缺氧、酸中毒和高细胞间压力的允许癌细胞环境，同时为 T 细胞浸润生成物理屏障，从而促进肿瘤发生和免疫抑制的肿瘤微环境。此外，最近的研究表明，形成肿瘤血管的血液内皮细胞可以积极抑制 T 细胞的募集、黏附和活性。同样，在肿瘤发生过程中，淋巴血管系统经历剧烈的重塑，促进癌细胞的转移扩散和免疫抑制。除了致癌作用外，不稳定的肿瘤血管最近还与治疗耐药机制有关，包括那些限制临床批准的免疫疗法（如免疫检查点抑制剂和过继性 T 细胞转移）疗效的机制。在这篇综述中，我们讨论了新出现的证据，强调了肿瘤相关的血液和淋巴管在阻止免疫监视机制和抗肿瘤免疫方面所起的主要作用。此外，我们还讨论了针对肿瘤血管的新型治疗方法及其帮助克服免疫治疗耐药性的潜力。
