免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
多发性转移的肿瘤突变负荷高黑色素瘤患者新抗原谱的特征分析
英文原题：Characterization of the Neoantigen Profile in a Tumor Mutation Burden-high Melanoma Patient With Multiple Metastases.
查看英文原题
Characterization of the Neoantigen Profile in a Tumor Mutation Burden-high Melanoma Patient With Multiple Metastases.
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研究概要
这些结果可能提示驱动基因突变的异质性不显著，而转移部位的免疫反应具有可变性。因此，基因组和免疫学研究为更好的癌症治疗决策提供了非常有价值且信息丰富的建议。
研究思路结论见上方概要
背景
最近，新抗原（NA）分析已被广泛应用于新型免疫疗法的开发。我们之前报道了一例高肿瘤突变负荷的黑色素瘤病例，该病例在接受抗程序性死亡-1治疗后实现了完全缓解。我们在此重新审视了同一病例，利用计算机算法和体外CTL实验表征了其他转移病灶的NA谱，并研究了转移部位的免疫状态，包括TIL（肿瘤浸润淋巴细胞）和T细胞受体（TCR）谱。
方法
从全外显子组测序获得的NA候选物被应用于HLA结合预测算法NetMHCpan4.1。选取了具有强结合能力（<50 nM）和洗脱亲和力（<1%）的HLA-A*2402限制性序列候选物，并对合成肽候选物进行了评估。通过基因表达谱分析、免疫组织化学和TCR库分析，对转移部位的免疫状态进行了表征。
结果
基因组分析显示，所有转移部位，如肋、肌内和脑病灶，均有>1,500个SNV，且12个驱动突变在所有部位中均存在。在肌内转移（KMT2C: p.P3292S）和脑转移（JAK1: p.S404P）中发现了新的驱动突变，对这些突变的功能分析显示，JAK1突变对侵袭活性具有促进作用。使用合成NA肽进行的CTL试验在脑转移中鉴定出更多的NA表位。
展开英文摘要原文
MATERIALS AND METHODS
NA candidates obtained from whole-exome sequencing were applied to the HLA-binding prediction algorithm, NetMHCpan4.1. HLA-A*2402-restricted sequence candidates with a strong binding capacity (<50 nM) and elution affinity (<1%) were selected and evaluated for synthetic peptide candidates. The immunological status in metastatic sites was characterized using gene expression profiling, immunohistochemistry, and a TCR repertoire analysis.
RESULTS
The genomic analysis revealed that all metastatic sites, such as costal, intra-muscular, and brain lesions, had >1,500 SNVs, and 12 driver mutations were common to all sites. New driver mutations were identified in intra-muscular (KMT2C: p.P3292S) and brain (JAK1: p.S404P) metastases and a functional analysis of these mutations revealed that JAK1 mutation exhibited a promoting effect on invasion activity. CTL assays using synthetic NA peptides identified more NA epitopes in brain metastasis.
CONCLUSION
These results might suggest that the heterogeneity of driver gene mutations is unremarkable, while immunological response is variable in metastatic sites. As a result, the genomic and immunological investigation has provided a very valuable and informative suggestion regarding better cancer therapy decisions.
论文信息
- 作者
- Yoshikawa S、Maeda C、Iizuka A、Ikeya T、Yamashita K、Ashizawa T、Kanematsu A、Miyata H
- 第一作者单位
- Division of Dermatology, Shizuoka Cancer Center Hospital, Shizuoka, Japan.Japan
- 通讯作者单位
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan; y.akiyama@scchr.jp.Japan
- 期刊
- Cancer genomics & proteomics2025 May-Jun
- 原文标识
- PubMed 40280722 · DOI 10.21873/cgp.20517
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