Tumor mutation burden, immune checkpoint crosstalk and radiosensitivity in single-cell RNA sequencing data of breast cancer
Tumor mutation burden, immune checkpoint crosstalk and radiosensitivity in single-cell RNA sequencing data of breast cancer
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DOI：
10.1016/j.radonc.2019.11.003
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发表时间：
2020-01-01
影响因子：
5.7
通讯作者：
Kim, In Ah
中科院分区：
文献类型：
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作者：
Jang, Bum-Sup;Han, Wonsik;Kim, In Ah
前言：我们利用来自乳腺癌和免疫细胞的scRNA-seq数据分析了转录和突变谱，主要集中在肿瘤突变负荷(TMB)、免疫检查点串扰和辐射敏感性。材料和方法：scRNA-seq转录组数据来自GEO数据库(GSE75688)。用放射敏感性指数(RSI)评价细胞的放射敏感性。用CD274mRNA的表达代替PD-L1的表达状态。对于免疫和肿瘤细胞组(N=492)，使用计算方法来确定关于免疫检查点配体-受体基因对的肿瘤和免疫细胞之间的潜在相互作用。突变数据来自从原发肿瘤和转移淋巴结(N=317)获得的肿瘤细胞的原始scRNA-seq数据。比较放射敏感性(RS)和放射抵抗(RR)肿瘤细胞的TMB和突变特征。结果：大多数RR细胞为基本亚型，PD-L1阳性率较高。TNBC或HER2亚型患者肿瘤与免疫细胞之间的免疫检查点配体-受体相互作用增加。与腔型患者相比，HER2亚型患者肿瘤细胞和T细胞之间的PD-L1配体-受体相互作用显著增加。同时，在具有TNBC亚型的患者中，CTLA-4配体与受体的相互作用增加。RR细胞的TMB显著高于RS细胞。RR细胞的微卫星不稳定性(MSI)和NRF2通路等突变特征发生改变。结论：RR细胞具有基本亚型，高PD-L1表达，高TMB，并有突变特征。肿瘤和免疫细胞之间的差异性串扰与乳腺癌患者的亚型有关。这些发现可能有助于确定潜在的生物标记物(S)以及免疫检查点阻断和放射治疗在乳腺癌治疗中的最佳组合策略。(C)2019爱思唯尔B.V.保留所有权利。
Introduction: We analyzed transcriptional and mutational profile mainly focused on tumor mutation burden (TMB), immune checkpoint crosstalk, and radiosensitivity using scRNA-seq data derived from breast cancer and immune cells.Materials and methods: scRNA-seq transcriptome data were acquired from the GEO database (GSE75688). The radiosensitivity index (RSI) was used to evaluate radiosensitivity of each cell. CD274 mRNA expression was used to surrogate PD-L1 expression status. A computational approach was utilized for the immune and tumor cell group (N = 492) to identify potential interactions between tumor and immune cells with respect to immune checkpoint ligand-receptor gene pairs. Mutation data was profiled from raw scRNA-seq data of tumor cells acquired from both primary tumor and metastatic lymph node (N = 317). TMB and mutational signatures were compared between radiosensitive (RS) and radioresistant (RR) tumor cells.Results: Most RR cells were a basal subtype and showed the higher rate of PD-L1 positivity. The patients with TNBC or HER2 subtype showed increased number of immune checkpoint ligand-receptor interactions between tumor and immune cells. PD-L1 ligand-receptor interactions between tumor cells and T cells were differentially increased in patients with the HER2 subtype compared to patients with the luminal subtype. Meanwhile, CTLA-4 ligand-receptor interactions were increased in patients with the TNBC subtype. TMB was significantly higher in RR cells than RS cells. Mutational signatures including microsatellite instability (MSI) and NRF2 pathway were altered in RR cells.Conclusions: RR cells exhibited a basal subtype, high PD-L1 expression, and high TMB with mutational signature found in tumors having MSI. Differential crosstalk between tumor and immune cells was associated with the patient subtype of breast cancer. These findings could be useful to identify potential biomarker(s) and optimal combination strategies of immune checkpoint blockades and radiation therapy in the management of breast cancer. (C) 2019 Elsevier B.V. All rights reserved.