Abstract

While sarcoma immunology has advanced with regard to basic, and even some applied topics, this disease has not been subject to more recent immunogenomics approaches. Thus, we assessed the immune receptor recombinations available from the cancer genome atlas (TCGA) sarcoma database via tumor sample exome and RNASeq files. Results indicated that recovery of T-cell receptor-alpha recombination reads (TRA) correlated with a better survival rate, with the expression of T-cell biomarkers, and with tumor sample apoptosis signatures consistent with the longer patient survival times. Furthermore, samples representing TRA complementarity determining region-3 (CDR3) net charge per residue (NCPR) based complementarity with the corresponding sarcoma mutanome had a better survival rate, and more granzyme expression, than samples lacking such complementarity. By specifically using RNASeq-recovered TRA CDR3s and related NCPR assessments, three genes, TP53, ATRX, and RB1, were identified as being key components of the mutanome-based complementarity. Thus, these genes may represent key immune system targets for soft tissue sarcomas. Also, several key results from above were reproduced with a pediatric osteosarcoma dataset, work that led to identification of MUC6 mutations as potentially linked to a strong immune response. In sum, TRA CDR3s are likely to be important prognostic indicators, and possibly a beginning tool for immunotherapy development strategies, for adult and pediatric sarcomas.

摘要

虽然肉瘤免疫学在基本甚至某些应用主题方面都取得了进步，但该疾病尚未受到最新的免疫基因组学方法的研究。因此，我们通过肿瘤样本外显子组和RNASeq文件评估了可从癌症基因组图谱（TCGA）肉瘤数据库获得的免疫受体重组。结果表明，T细胞受体-α重组读数（TRA）的恢复与更好的生存率，T细胞生物标志物的表达以及与更长的患者生存时间一致的肿瘤样本凋亡特征相关。此外，与缺乏这种互补性的样品相比，代表基于每个残基的TRA互补决定区3（CDR3）净电荷（NCPR）与相应的肉瘤突变的互补性样品具有更好的存活率和更多的颗粒酶表达。通过专门使用RNASeq恢复的TRA CDR3和相关的NCPR评估，三个基因TP53，ATRX和RB1被确定为基于诱变的互补性的关键组成部分。因此，这些基因可能代表了软组织肉瘤的关键免疫系统靶标。此外，儿科骨肉瘤数据集还再现了以上的一些关键结果，这项工作导致将MUC6突变鉴定为可能与强免疫反应有关。总之，TRA CDR3可能是成人和小儿肉瘤的重要预后指标，并且可能是免疫疗法发展策略的起始工具。这些基因可能代表了软组织肉瘤的关键免疫系统靶标。此外，儿科骨肉瘤数据集还再现了以上的一些关键结果，这项工作导致将MUC6突变鉴定为可能与强免疫反应有关。总之，TRA CDR3可能是成人和小儿肉瘤的重要预后指标，并且可能是免疫疗法发展策略的起始工具。这些基因可能代表了软组织肉瘤的关键免疫系统靶标。此外，儿科骨肉瘤数据集还再现了以上的一些关键结果，这项工作导致将MUC6突变鉴定为可能与强免疫反应有关。总之，TRA CDR3可能是成人和小儿肉瘤的重要预后指标，并且可能是免疫疗法发展策略的起始工具。