Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments
Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments
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DOI：
10.1002/hep.32201
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发表时间：
2021-12-12
期刊：
影响因子：
13.5
通讯作者：
Sakamoto, Michiie
中科院分区：
文献类型：
--
作者：
Kurebayashi, Yutaka;Matsuda, Kosuke;Sakamoto, Michiie
背景和目的免疫细胞和肿瘤血管构成肿瘤组织的重要组成部分;然而，它们在人类肿瘤（包括HCC）中的详细关系在很大程度上仍然未知。因此，我们扩展了我们以前对HCC免疫微环境的研究，并分析了免疫微环境、炎症/血管生成抑制因子表达、血管生成因子表达和肿瘤血管发现之间的关系，包括血管包裹肿瘤簇（VETC）和大小梁-块状（MTM）模式。方法和结果我们将HCC分为四种不同的免疫血管亚型（免疫高/血管抑制[IH/AS]、免疫中/血管中[IM/AM]、免疫低/血管生成[IL/AG]和免疫低/血管低[IL/AL]）。IH/AS、IM/AM和IL/AG亚型与减少淋巴细胞浸润和增加血管生成因子表达和VETC/MTM阳性相关，反映了它们在HCC肿瘤微环境中的相互作用。IL/AG亚型的进一步特征是CTNNB 1突变和Wnt/β-连环蛋白途径的激活。IL/AL亚型与淋巴细胞浸润或血管生成因子表达增加无关。在两个独立队列中，IH/AS亚型和VETC/MTM阳性的预后独立显著。血管生成因子表达增加与VETC/MTM阳性和不良预后不一定相关，特别是当肿瘤血管周围炎性/血管生成抑制环境共存时。这些结果可能提供对免疫疗法，抗血管生成疗法及其组合的治疗效果的见解。评估免疫血管微环境在预测这些治疗在不可切除的HCC中的临床效果方面的潜力需要在未来的研究中进行分析。结论HCC可分为4种不同的免疫血管亚型（IH/AS、IM/AM、IL/AG和IL/AL），反映了抗肿瘤免疫微环境与肿瘤血管生成之间的相互作用。除了其临床病理学意义外，免疫血管分类还可以为免疫治疗、抗血管生成治疗及其组合的治疗效果提供病理学见解。
Background and Aims Immune cells and tumor vessels constitute important elements in tumor tissue; however, their detailed relationship in human tumors, including HCC, is still largely unknown. Consequently, we expanded our previous study on the immune microenvironment of HCC and analyzed the relationship among the immune microenvironment, inflammatory/angiostatic factor expression, angiogenic factor expression, and tumor vessel findings, including vessels encapsulating tumor clusters (VETC) and macrotrabecular-massive (MTM) patterns. Approach and Results We classified HCC into four distinct immunovascular subtypes (immune-high/angiostatic [IH/AS], immune-mid/angio-mid [IM/AM], immune-low/angiogenic [IL/AG], and immune-low/angio-low [IL/AL]). IH/AS, IM/AM, and IL/AG subtypes were associated with decreasing lymphocytic infiltration and increasing angiogenic factor expression and VETC/MTM positivity, reflecting their reciprocal interaction in the tumor microenvironment of HCC. IL/AG subtype was further characterized by CTNNB1 mutation and activation of Wnt/beta-catenin pathway. IL/AL subtype was not associated with increased lymphocyte infiltration or angiogenic factor expression. Prognostically, IH/AS subtype and VETC/MTM positivity were independently significant in two independent cohorts. Increased angiogenic factor expression was not necessarily associated with VETC/MTM positivity and poor prognosis, especially when inflammatory/angiostatic milieu coexisted around tumor vessels. These results may provide insights on the therapeutic effects of immunotherapy, antiangiogenic therapies, and their combinations. The potential of evaluating the immunovascular microenvironment in predicting the clinical effect of these therapies in nonresectable HCC needs to be analyzed in the future study. Conclusions HCC can be classified into four distinct immunovascular subtypes (IH/AS, IM/AM, IL/AG, and IL/AL) that reflect the reciprocal interaction between the antitumor immune microenvironment and tumor angiogenesis. In addition to its clinicopathological significance, immunovascular classification may also provide pathological insights on the therapeutic effect of immunotherapy, antiangiogenic therapy, and their combination.