Comment on ‘Tumour antigen expression in hepatocellular carcinoma in a low-endemic western area'

F Grizzi; D Qehajaj; M Chiriva-Internati; S Stifter

摘要

Sir, We read with great interest the study by Sideras et al (2015) that combines tissue microarrays (TMA) and immunohistochemistry to investigate the expression pattern of 15 antigens belonging to different categories, including cancer testis antigens (CTAs) and oncofetal proteins in primary hepatocellular carcinoma (HCC). Because current therapies for HCC are far from ideal ( Ilan, 2014 ) and immunotherapy has been proposed as a potential therapeutic option, the authors aimed at identifying a panel of relevant tumour antigens with broad expression in a Western European population of HCC patients and specific expression in the tumour tissue ( Sideras et al , 2015 ). Cancer testis antigens represent a family of >200 proteins selectively expressed in malignant cells, but not in their natural counterpart except for human germ cells ( Simpson et al , 2005 ; Gjerstorff et al , 2015 ; Grizzi et al , 2015 ). Among the different types of tumour antigens, CTAs identified highly promising therapeutic targets ( Gjerstorff et al , 2015 ). In contrast to previous studies ( Xu et al , 2012 ; Liang et al , 2013 ; Xia et al , 2013 ; Wang et al , 2015 ), Sideras et al (2015) found a low (<10% of patients) prevalence of expression of MAGE-A3/4, NY-ESO-1, MAGE-A1 and MAGE-A10. Moreover, a low ( 70% of HCC-affected patients have usually a high serum concentration of AFP. Today, AFP and ultrasonography are the main tests for HCC surveillance in clinical practice, and in the interim, using ultrasonography and AFP in combination may be the best strategy to optimise early HCC detection ( Mehta and Singal, 2015 ). Sideras et al (2015) stated that the observed prevalence of expression of CTAs and oncofetal antigens was generally lower because previous studies have been conducted in East Asia where hepatitis B virus infection is the prevalent cause of HCC and the majority of HCC patients have liver cirrhosis. Furthermore, previous investigators used RT–PCR measuring mRNA expression, whereas they evaluated protein expression by immunohistochemistry. Here, we would like to discuss additional points underlying these discrepancies and that impact on the CTAs as immunotherapeutic targets. In an effort to accelerate translation of new developments in basic immunology into cancer patients, representatives from eight immunotherapy organisations representing Europe, Japan, China and North America convened an ‘Immunotherapy Summit' at the 24th Annual Meeting of the International Society for Biological Therapy of Cancer (now called Society for Immunotherapy of Cancer, SITC). One of the concepts raised by SITC and defined as critical was the need to identify hurdles that impede effective translation of cancer immunotherapy ( Fox et al , 2011 ). The critical hurdles highlighted have been grouped into nine general themes. Among these have been identified the ‘complexity of cancer', its ‘heterogeneity' and ‘immune escape' ( Fox et al , 2011 ). Hepatocellular carcinoma originates and progresses throughout a dynamic process involving different ‘driven alterations' that ultimately lead to the malignant transformation of hepatocytes. Malignant transformation may occur regardless of the aetiologic agent through a pathway of increased liver cell turnover, induced by chronic liver injury and regeneration in a context of inflammation, immune response and oxidative DNA damage ( Li and Wang, 2015 ). Hepatocellular carcinoma is a heterogeneous disease in ‘space' and in ‘time'. The term ‘heterogeneity' defines the presence of cell clones, within a tumoral mass, with different genetic aberrations that mediate divergent biology defining the natural history of that particular tumour, that is, one clone does not represent the entirety of the tumour cell population. This variability is what ultimately determines the evolutionary progression of neoplastic disease and its response to therapy ( Luo et al , 2009 ). Singular cells respond differently to the same stimulus, with some not responding at all ( Floor et al , 2012 ; Almendro et al , 2013 ). These considerations, in conjunction with the complexity of ‘tumour–host' interactions caused by temporal changes in tumour phenotypes and an array of immune mediators expressed in the tumour microenvironment, might explain the limited reliability and applicability of current therapeutic strategies. Sideras et al (2015) did not report fundamental hallmarks of cancer, including ‘cancer complexity', ‘tumour heterogeneity' and ‘field cancerization', that is, the presence of abnormal tissue surrounding primary cancerous lesions. These observations lead us to reflect on the appropriateness of TMAs to state the CTAs and oncofetal proteins as potential therapeutic targets. It is known that diagnostic accuracy of a histological assay may be affected if the ‘target antigen' is uniquely present in a fraction of a tumour ( Sottoriva et al , 2015 ). Tissue microarray consists of small fractions of tissue inserted into a recipient para

机译：主席先生，我们非常感兴趣，阅读了Sideras等人（2015）的研究，该研究结合了组织微阵列（TMA）和免疫组织化学，研究了15种不同类别抗原的表达模式，其中包括癌睾丸抗原（CTA）和癌胚蛋白在原发性肝癌中的表达。肝细胞癌（HCC）。由于目前的HCC治疗方法远非理想（Ilan，2014），并且已提出免疫治疗作为潜在的治疗选择，因此作者旨在鉴定一组在西欧HCC患者中广泛表达且特异性表达的相关肿瘤抗原在肿瘤组织中（Sideras等人，2015）。癌症睾丸抗原代表在恶性细胞中选择性表达的> 200个蛋白家族，但除人类生殖细胞以外，在其天然对应物中不表达（Simpson等，2005; Gjerstorff等，2015; Grizzi等，2015）。在不同类型的肿瘤抗原中，CTA确定了高度有前途的治疗靶点（Gjerstorff等，2015）。与之前的研究相反（Xu et al，2012; Liang et al，2013; Xia et al，2013; Wang et al，2015），Sideras et al（2015）发现低表达率（<10％的患者） MAGE-A3 / 4，NY-ESO-1，MAGE-A1和MAGE-A10的图片。此外，低（70％受HCC影响的患者通常血清AFP较高）。今天，AFP和超声检查是临床实践中进行HCC监测的主要测试，在此期间，超声检查和AFP的结合使用可能会优化早期HCC检测的最佳策略（Mehta和Singal，2015年）Sideras等人（2015年）指出，观察到的CTAs和胎粪抗原表达的患病率普遍较低，因为先前在东亚进行过乙肝病毒研究感染是肝癌的普遍病因，大多数肝癌患者都患有肝硬化;此外，以前的研究人员使用RT–PCR测量mRNA表达，而他们通过免疫组织化学评估了蛋白表达。在这里，我们想讨论这些差异和会影响作为免疫治疗靶点的CTAs，以加速将基础免疫学的新进展转化为癌症患者，来自欧洲，日本，中国和北美的八个免疫疗法组织的代表在国际癌症生物疗法学会（现称为SITC）第24届年会上召开了“免疫疗法峰会”。 SITC提出并定义为关键的概念之一是需要确定阻碍癌症免疫疗法有效翻译的障碍（Fox等，2011）。突出显示的关键障碍分为九个总体主题。其中已确定为“癌症的复杂性”，“异质性”和“免疫逃逸”（Fox等，2011）。肝细胞癌在涉及不同“驱动性改变”的整个动态过程中起源和发展，最终导致肝细胞的恶性转化。无论是哪种病原菌，均可通过增加肝细胞更新的途径发生恶性转化，这种途径是由慢性肝损伤和炎症，免疫反应和氧化性DNA损伤引起的再生引起的（Li和Wang，2015）。肝细胞癌是“时空”和“时空”的异质性疾病。术语“异质性”定义了在肿瘤块中存在具有不同遗传畸变的细胞克隆，这些遗传畸变介导了定义该特定肿瘤自然历史的不同生物学，也就是说，一个克隆并不代表整个肿瘤细胞群体。这种可变性最终决定了肿瘤疾病的发展进程及其对治疗的反应（Luo等，2009）。单个细胞对相同刺激的反应不同，有些根本不响应（Floor等，2012; Almendro等，2013）。这些考虑因素，再加上由肿瘤表型的时间变化和在肿瘤微环境中表达的一系列免疫介质引起的“肿瘤-宿主”相互作用的复杂性，可以解释当前治疗策略的有限的可靠性和适用性。 Sideras等人（2015年）未报告癌症的基本特征，包括“癌症复杂性”，“肿瘤异质性”和“场癌化”，即原发癌病变周围存在异常组织。这些观察结果使我们反思了TMA是否将CTAs和癌胚蛋白列为潜在治疗靶标的适当性。众所周知，如果“靶抗原”独特地存在于肿瘤的一部分中，则可能会影响组织学测定的诊断准确性（Sottoriva等，2015）。组织微阵列由一小部分组织插入受体段

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