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Abstract：
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.
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.
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.
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.
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.
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.
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.
摘要：
尽管突变的HLA配体被认为是理想的癌症特异性免疫疗法靶标，在肝细胞癌（HCC）中缺乏其表现的证据。采用独特的多组学方法，包括新表位鉴定管道，我们评估了在HCCs中天然呈现为HLAI类配体的外显子组衍生突变.
深入的多组学分析包括全外显子组和转录组测序，以定义新表位候选物的个体患者特异性搜索空间。通过整合蛋白质组和HLA配体谱分析数据的计算机流水线研究了突变的HLA配体的自然呈递的证据。
该方法已在来自恶性黑色素瘤的最新数据集中成功验证，尽管存在体细胞突变的多组学证据,突变的天然呈递的HLA配体在HCC中仍然难以捉摸。对大量癌症数据集的分析证实了HCC和恶性黑色素瘤中肿瘤突变负担的基本差异，在只有很少突变的恶性肿瘤中，外显子组衍生的突变与预期的新表位池相关的观点提出了挑战。
这项研究表明，外显子组衍生的突变HLA配体似乎很少出现在HCC中，尤其是由于与其他恶性肿瘤如恶性黑素瘤相比的低突变负担。因此，我们的结果需要扩大个性化免疫疗法的目标范围，超越突变的新表位的有限范围。特别是对于具有相似或较低突变负担的恶性肿瘤。
深入的多组学分析包括全外显子组和转录组测序，以定义新表位候选物的个体患者特异性搜索空间。通过整合蛋白质组和HLA配体谱分析数据的计算机流水线研究了突变的HLA配体的自然呈递的证据。
该方法已在来自恶性黑色素瘤的最新数据集中成功验证，尽管存在体细胞突变的多组学证据,突变的天然呈递的HLA配体在HCC中仍然难以捉摸。对大量癌症数据集的分析证实了HCC和恶性黑色素瘤中肿瘤突变负担的基本差异，在只有很少突变的恶性肿瘤中，外显子组衍生的突变与预期的新表位池相关的观点提出了挑战。
这项研究表明，外显子组衍生的突变HLA配体似乎很少出现在HCC中，尤其是由于与其他恶性肿瘤如恶性黑素瘤相比的低突变负担。因此，我们的结果需要扩大个性化免疫疗法的目标范围，超越突变的新表位的有限范围。特别是对于具有相似或较低突变负担的恶性肿瘤。
