Breast Cancer Unit at Department of Medical Oncology, Hospital Universitari i Politècnic La Fe, Valencia, Spain; Clinical and Translational Research in Cancer, Instituto de Investigación Sanitaria La Fe, Spain; Genomics Unit, Instituto de Investigación Sanitaria La Fe, Spain.
Breast Cancer Unit at Department of Medical Oncology, Hospital Universitari i Politècnic La Fe, Valencia, Spain; Clinical and Translational Research in Cancer, Instituto de Investigación Sanitaria La Fe, Spain.
Eur J Cancer. 2020 Nov;139:119-134. doi: 10.1016/j.ejca.2020.08.020. Epub 2020 Sep 29.
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.
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.
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.
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.
三阴性乳腺癌（TNBC）的特点是对新辅助化疗（NAC）有很高的病理完全缓解率。然而，难治性和 NAC 应答不良的患者仍然面临着非常差的预后，这强调了迫切需要能够帮助识别这些患者的工具，以便在治疗方案中尽早考虑手术或 NAC 的替代方案。
我们在 TNBC 患者诊断时结合代谢组学、外泌体循环 miRNA 和流式细胞术实验方法以及针吸活检肿瘤的免疫组织化学，生成 NAC 反应预测模型。我们还共培养了分离的患者来源的早期髓系来源的抑制细胞（eMDSCs）和 TNBC 癌细胞系，并研究了它们之间的串扰。
血液衍生的液体活检生物标志物显示出一种新型的色氨酸衍生代谢物和 eMDSC 水平的免疫抑制谱，这些标志物显著预测了 NAC 反应。值得注意的是，肿瘤细胞中的吲哚胺 2,3-双加氧酶 1（IDO1）表达与循环色氨酸水平呈负相关，但与 eMDSC 水平呈正相关。此外，一组靶向免疫成熟途径的循环外泌体 miRNA 也在化疗前预测了不良的 NAC 反应。有趣的是，当 TNBC 细胞系与患者来源的 eMDSCs 共培养时，IDO1 的表达增加，而这反过来又促进了 eMDSCs 的增殖。
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。我们发现了肿瘤细胞和 eMDSCs 之间的串扰机制，加剧了免疫抑制。这些结果为识别 NAC 应答不良的患者提供了一种潜在的新工具，以便为其提供替代治疗策略，包括早期手术切除肿瘤，并探索替代免疫治疗。
