减少三阴性乳腺癌化疗耐药的新方法

　　三阴性乳腺癌与其他乳腺癌相比，全身治疗主要依靠高强度细胞毒性化疗，而且容易发生耐药，故预后较差。由于肿瘤基质存在大量癌症相关成纤维细胞，故英国学者推测癌症相关成纤维细胞可能对化疗敏感或耐药具有调节作用。

　　2021年1月4日，英国癌症研究基金会《英国癌症杂志》在线发表英国利兹大学、利兹教学医院、圣詹姆斯医院的研究报告，探讨了乳腺成纤维细胞对三阴性乳腺癌化疗敏感或耐药的调节机制。

　　该研究将乳腺成纤维细胞与三阴性乳腺癌细胞（MDA-MB-231、MDA-MB-157、MDA-MB-468）共同培养，利用荧光素酶或克隆形成法对化疗后的细胞存活进行定量，利用转录组学、报道蛋白、重组蛋白、阻断抗体、免疫组织化学法对信号传导及其临床意义进行分析。

　　结果发现，乳腺癌相关成纤维细胞数量与三阴性乳腺癌细胞MDA-MB-231和MDA-MB-157化疗耐药成正比，对MDA-MB-468影响不大。此外，癌症相关成纤维细胞诱发的化疗耐药与干扰素激活成正比。

　　将化疗药物与三阴性乳腺癌共同培养，可诱导癌症相关成纤维细胞表达干扰素β1，从而引起癌细胞旁分泌激活。利用基因重组干扰素，也可引起三阴性乳腺癌细胞MDA-MB-231和MDA-MB-157化疗耐药，对MDA-MB-468影响不大。

　　对于三阴性乳腺癌患者，癌症相关成纤维细胞干扰素β1表达水平与癌细胞干扰素信号传导被激活的标志物MX1表达水平成正比。癌症相关成纤维细胞干扰素β1或癌细胞MX1高表达与低表达相比，三阴性乳腺癌患者化疗后无病生存时间显著较短，尤其密封蛋白低表达肿瘤（MDA-MB-231和MDA-MB-157）。

　　利用阿斯利康研制用于阻断干扰素受体以治疗红斑狼疮的单克隆抗体anifrolumab可显著减少癌症相关成纤维细胞所致化疗耐药。

　　因此，该研究结果表明，癌症相关成纤维细胞诱发的密封蛋白低表达三阴性乳腺癌干扰素信号传导激活可引起化疗耐药，抑制干扰素信号传导通路有望成为改善三阴性乳腺癌患者生存结局的新方法。

Br J Cancer. 2021 Jan 4. Online ahead of print.

Inhibition of interferon-signalling halts cancer-associated fibroblast-dependent protection of breast cancer cells from chemotherapy.

Robyn V. Broad, Stacey J. Jones, Melina C. Teske, Laura M. Wastall, Andrew M. Hanby, James L. Thorne, Thomas A. Hughes.

University of Leeds, Leeds, UK; Leeds Teaching Hospitals NHS Trust, Leeds, UK; St. James's University Hospital, Leeds, UK.

BACKGROUND: Triple negative breast cancers (TNBC) have poor prognoses despite aggressive treatment with cytotoxic chemotherapy. Cancer-associated fibroblasts (CAFs) are prominent in tumour stroma. Our hypothesis was that CAFs modulate chemotherapy sensitivity.

METHODS: TNBC cells and breast fibroblasts were cultured; survival after chemotherapeutics was assessed using luciferase or clonogenic assays. Signalling was investigated using transcriptomics, reporters, recombinant proteins and blocking antibodies. Clinical relevance was investigated using immunohistochemistry.

RESULTS: Breast CAFs dose-dependently protected TNBC cell lines MDA-MB-231 and MDA-MB-157, but not MDA-MB-468s, from chemotherapy. CAF-induced protection was associated with interferon (IFN) activation. CAFs were induced to express IFNβ1 by chemotherapy and TNBC co-culture, leading to paracrine activation in cancer cells. Recombinant IFNs were sufficient to protect MDA-MB-231 and MDA-MB-157 but not MDA-MB-468 cells. In TNBC patients, IFNβ1 expression in CAFs correlated with cancer cell expression of MX1, a marker of activated IFN signalling. High expression of IFNβ1 (CAFs) or MX1 (tumour cells) correlated with reduced survival after chemotherapy, especially in claudin-low tumours (which MDA-MB-231 and MDA-MB-157 cells represent). Antibodies that block IFN receptors reduced CAF-dependent chemoprotection.

CONCLUSIONS: CAF-induced activation of IFN signalling in claudin-low TNBCs results in chemoresistance. Inhibition of this pathway represents a novel method to improve breast cancer outcomes.

DOI: 10.1038/s41416-020-01226-4