Immunosuppressive profiles in liquid biopsy at diagnosis predict response to neoadjuvant chemotherapy in triple-negative breast cancer
Immunosuppressive profiles in liquid biopsy at diagnosis predict response to neoadjuvant chemotherapy in triple-negative breast cancer
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DOI：
10.1016/j.ejca.2020.08.020
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发表时间：
2020-11-01
影响因子：
8.4
通讯作者：
Font de Mora, Jaime
中科院分区：
文献类型：
--
作者：
Salvador-Coloma, Carmen;Santaballa, Ana;Font de Mora, Jaime
背景：三阴性乳腺癌（TNBC）的特征是对新辅助化疗（NAC）的高度病理完全反应。然而，难治性和差的NAC应答者仍然面临非常差的结果，强调迫切需要有助于识别这些患者的工具，以便在治疗方案中早期考虑手术或NAC的替代方案。材料和方法：我们结合了代谢组学，外泌体循环miRNA和流式细胞术实验方法在TNBC患者中在诊断时用针穿刺活检肿瘤中的免疫组织化学产生NAC-响应预测模型我们还共同培养和研究孤立的患者来源的早期骨髓来源的抑制细胞（eMDSC）和TNBC癌细胞line.Results之间的串扰：血液来源的液体活检生物标志物显示一种新的免疫抑制概况的Dahan衍生的代谢物和eMDSC水平，显着预测NAC的反应。值得注意的是，肿瘤细胞中吲哚胺2，3-双加氧酶1（IDO 1）的表达与循环色氨酸水平呈负相关，但与eMDSC的水平直接相关。此外，一组靶向免疫成熟途径的循环外泌体miRNA也预测了化疗前NAC反应不良。有趣的是，IDO 1的表达增加时，TNBC细胞系与患者来源的eMDSCs共培养，这反过来又促进了eMDSCs的增殖。结论：我们的研究结果表明，免疫系统的抑制途径在调节TNBC的NAC反应中起着关键作用。我们确定了肿瘤细胞和eMDSC之间的串扰机制，加剧了免疫抑制。这些结果提供了一个潜在的新工具，以确定穷人的NAC反应的替代治疗策略，包括早期手术切除肿瘤，并探讨他们的替代免疫疗法。(C)2020年，任作家。由爱思唯尔有限公司发布
Background: Triple-negative breast cancer (TNBC) is characterised by high pathological complete response to neoadjuvant chemotherapy (NAC). However, refractory and poor NAC responders still face very poor outcome, emphasising the urgent need for tools that facilitate identification of these patients, so that surgery or alternatives to NAC are considered early in the treatment protocol.Materials and methods: We combined metabolomics, exosome circulating miRNAs and flow cytometry experimental approaches in TNBC patients at diagnosis with immunohistochemistry in needle biopsy tumours to generate NAC-response predictive models. We also co-cultured and studied crosstalk between isolated patient-derived early myeloid-derived suppressor cells (eMDSCs) and TNBC cancer cell lines.Results: Blood-derived liquid biopsy biomarkers display a novel immunosuppressive profile of tryptophan-derived metabolites and eMDSC levels that significantly predict NAC response. Notably, indoleamine 2,3-dioxygenase 1 (IDO1) expression in tumour cells inversely correlated with circulating tryptophan levels but directly correlated with the level of eMDSCs. In addition, a set of circulating exosome miRNAs that target pathways of immune maturation also predicted poor NAC response prior to chemotherapy. Interestingly, expression of IDO1 increased when TNBC cell lines were co-cultured with patient-derived eMDSCs and this, in turn, promoted proliferation of eMDSCs.Conclusion: Our findings demonstrate that the suppressive pathways of the immune system play a key role in modulating the NAC response in TNBC. We identify a crosstalk mechanism between tumour cells and eMDSCs that exacerbates immunosuppression. These results provide a potential new tool to identify poor NAC responders for alternative strategies of treatment, including early surgical resection of the tumour, and to explore in them alternative immune therapies. (C) 2020 The Authors. Published by Elsevier Ltd.