Desterke Christophe, Xiang Yao, Elhage Rima, Duruel Clémence, Chang Yunhua, Hamaï Ahmed
UFR Médecine-INSERM UMRS1310, Université Paris-Saclay, F-94800 Villejuif, France.
INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Université Paris Cité, F-75015 Paris, France.
Cancers (Basel). 2023 Dec 28;16(1):155. doi: 10.3390/cancers16010155.
(1) Background: Triple-negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting a high level of recurrence, and neo-adjuvant chemotherapy is beneficial in its therapy management. Anti-PD-L1 immunotherapy improves the effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis-related R-packages were developed for integrative omics analyses under ferroptosis-inducer treatments: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), single cell data (GSE191246) and mass spectrometry on breast cancer stem cells. Clinical association analyses were carried out with breast tumors (TCGA and METABRIC cohorts). Protein-level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers upregulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated with overall survival. Breast tumors presenting high expression of CD274 upregulated some ferroptosis drivers associated with prognosis: IDO1, IFNG and TNFAIP3. At the protein level, the induction of Cd274 and Tnfaip3 was confirmed in breast cancer stem cells under salinomycin treatment. In a 4T1 tumor treated with cyclophosphamide, the single cell expression of Cd274 was found to increase both in myeloid- and lymphoid-infiltrated cells, independently of its receptor Pdcd1. The CD274 ferroptosis-driver score computed on a breast tumor transcriptome stratified patients on their prognosis: low score was observed in the basal subgroup, with a higher level of recurrent risk scores (oncotypeDx, ggi and gene70 scores). In the METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found to be overexpressed in the TNBC subgroup. The CD274 ferroptosis-driver score was found to be associated with overall survival, independently of TNM classification and age diagnosis. The tumor expression of CD274, TNFAIP3, IFNG and IDO1, in a biopsy of breast ductal carcinoma, was confirmed at the protein level (4) Conclusions: Ferroptosis inducers upregulate PD-L1 in TNBC cells, known to be an effective target of immunotherapy in high-risk early TNBC patients who received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. The CD274 ferroptosis-driver score is associated with prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested for recurrent TNBC.
(1) 背景：三阴性乳腺癌（TNBC）是乳腺癌的一个独特亚组，具有高复发率，新辅助化疗对其治疗管理有益。抗程序性死亡配体1（PD-L1）免疫疗法可改善TNBC新辅助治疗的效果。(2) 方法：开发了免疫调节和铁死亡相关的R包，用于在铁死亡诱导剂处理下进行综合组学分析：用铁死亡诱导剂刺激TNBC细胞（GSE173905、GSE154425）、单细胞数据（GSE191246）以及对乳腺癌干细胞进行质谱分析。对乳腺肿瘤（癌症基因组图谱和分子特征数据库队列）进行临床关联分析。通过蛋白质图谱蛋白质组实验研究蛋白质水平的验证。(3) 结果：艾拉司群/RSL3铁死亡诱导剂可上调TNBC细胞（MDA-MB-231和HCC38）中的CD274。在乳腺癌中，CD274表达与总生存期相关。CD274高表达的乳腺肿瘤上调了一些与预后相关的铁死亡驱动因子：吲哚胺2,3-双加氧酶1（IDO1）、干扰素γ（IFNG）和肿瘤坏死因子α诱导蛋白3（TNFAIP3）。在蛋白质水平上，盐霉素处理下的乳腺癌干细胞中Cd274和Tnfaip3的诱导得到证实。在用环磷酰胺治疗的4T1肿瘤中，发现Cd274在髓系和淋巴系浸润细胞中的单细胞表达均增加，与其受体程序性死亡蛋白1（Pdcd1）无关。根据乳腺肿瘤转录组计算的CD274铁死亡驱动因子评分可对患者的预后进行分层：在基底亚组中观察到低评分，复发风险评分（Oncotype Dx、ggi和基因70评分）较高。在分子特征数据库队列中，发现CD274、IDO1、IFNG和TNFAIP3在TNBC亚组中过表达。发现CD274铁死亡驱动因子评分与总生存期相关，与肿瘤-淋巴结-转移（TNM）分期和年龄诊断无关。在乳腺导管癌活检中，CD274、TNFAIP3、IFNG和IDO1的肿瘤表达在蛋白质水平上得到证实。(4) 结论：铁死亡诱导剂可上调TNBC细胞中的PD-L1，已知PD-L1是接受新辅助治疗的高危早期TNBC患者免疫治疗的有效靶点。基底和TNBC肿瘤高表达CD274和铁死亡驱动因子：IFNG、TNFAIP3和IDO1。CD274铁死亡驱动因子评分与乳腺癌的预后和复发风险相关。对于复发性TNBC，建议铁死亡诱导剂与抗PD-L1免疫疗法具有潜在协同作用。
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