Hepatocellular carcinoma HLA HLA ligandomics Immunoinformatics Immunotherapy Liver cancer
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摘要

Abstract Background Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs. Methods In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data. Results The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somatic mutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignant melanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations. Conclusions This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignant melanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.

译文

摘要背景虽然突变的 HLA 配体被认为是理想的癌症特异性免疫治疗靶点,但在肝细胞癌 (HCCs) 中缺乏其表现的证据。采用独特的包括新表位鉴定管道的多组学方法,我们评估了在 HCCs 中自然表现为 HLA I 类配体的 exome 衍生突变。方法深入的多组学分析包括整个外表面组和转录组测序,以定义新表位候选者的个体患者特异性搜索空间。通过整合蛋白质组和 HLA 配体谱数据的计算机模拟流程,研究了突变 HLA 配体自然呈现的证据。结果该方法在来自恶性黑素瘤的最先进的数据集上得到成功验证,尽管有体细胞突变的多组学证据,但突变的自然呈现的 HLA 配体在 HCCs 中仍然难以捉摸。广泛的癌症数据集的分析证实了肝癌和恶性黑素瘤中肿瘤突变负担的基本差异, 挑战只有少数突变的恶性肿瘤中,exome 衍生的突变有助于相关的可预期的新抗原库的概念。结论这项研究表明,与其他恶性肿瘤如恶性黑素瘤相比,基因突变型的 HLA 配体似乎很少出现在肝癌中,尤其是由低突变负担造成的。因此,我们的结果要求将个性化免疫治疗的目标范围扩大到突变新表位的有限范围之外,特别是对于具有相似或较低突变负担的恶性肿瘤。

hepatocellular carcinoma

消化 肝脏恶性肿瘤 疾病
概述  :  

肝细胞癌(hepatocellular carcinoma,HCC)是我国常见的恶性肿瘤,严重威胁我国国民健康。有统计数据表明,几乎每2例HCC患者,就有1例来自于中国。因此,加强HCC的预防、监测及治疗,在我国具有十分重要的意义。随着新型靶向药物以及免疫治疗在HCC治疗领域的不断成功,HCC治疗药物种类日益丰富,治疗策略不断更新,同时也为HCC治疗带来了新的机遇与挑战。 肝细胞癌流行病学特征(1)在过去20年中,HCC发病率在世界范围内不断上升,预计到2030年,包括美国在内的一

hepatocellular /,hepətəu'seljulə/

释义   adj. 肝细胞的

例句   Hepatocellular carcinoma (HCC) is serious harmto human health, and world-wide is one ofthe most common malignant tumors. 

肝细胞癌(HCC)是严重危害人类健康、也是全世界范围内最常见的恶性肿瘤之一。


carcinoma 英 /ˌkɑːsɪˈnəʊmə/  美 /ˌkɑːrsɪˈnoʊmə/

释义   n. [肿瘤] 癌

例句   So if this is an example of lobular carcinoma, i think it is very atypical . 

因此,这例如果是小叶癌,我认为是一种非常不典型的病例。


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