Metastasis is the major cause of death for patients with triple-negative breast cancer and other solid malignancies. Metastases arise from cancer cells that disseminate from the original tumour, survive systemic immune surveillance and colonize new organs1. Little is known about how initial disseminated tumour cells (DTCs) overcome anti-tumour immunity after seeding a new organ. Here we use a visible antigen in a model of triple-negative breast cancer with cognate CD8+ T cells to study the mechanisms of immune evasion in early metastatic seeding. Analysis of surviving DTCs revealed glucocorticoid receptor (GR) activation as a key driver of resistance to both CD8+ T cells and natural killer cells. Niche profiling using an optimized labelling tool identified FAS–FASL as a key pan-cytotoxic pathway against DTCs, which is repressed by GR activation. Pharmacological inhibition of GR in combination with immunotherapy reduced metastatic burden and expanded lifespan in mice. Thus, we identified a mechanism of immune evasion that operates specifically in DTCs, illustrating the unique immune–cancer interactions at this stage in the metastatic cascade. Our findings suggest that there are therapeutic opportunities to eliminate DTCs, separately from treatments aimed at primary tumours, and GR inhibition is one promising target.
转移是导致三阴性乳腺癌及其他实体恶性肿瘤患者死亡的主要原因。转移源于从原发肿瘤播散的癌细胞，这些细胞需在全身免疫监视中存活并定植于新器官。目前关于初始播散肿瘤细胞（DTCs）在定植新器官后如何克服抗肿瘤免疫的机制知之甚少。本研究利用三阴性乳腺癌模型中的可视化抗原及同源CD8+ T细胞，探究早期转移定植过程中的免疫逃逸机制。对存活DTCs的分析显示，糖皮质激素受体（GR）激活是驱动其对CD8+ T细胞和自然杀伤细胞产生抵抗的关键因素。通过优化标记工具进行的微环境分析发现，FAS-FASL是靶向DTCs的关键泛细胞毒性通路，而GR激活会抑制该通路。药理学抑制GR联合免疫治疗可减少小鼠转移负荷并延长生存期。因此，我们鉴定出DTCs特异性运作的免疫逃逸机制，揭示了转移级联反应中这一阶段的独特免疫-肿瘤相互作用。我们的发现表明，存在独立于原发性肿瘤治疗之外的靶向清除DTCs的治疗机会，而GR抑制正是具有前景的靶点之一。
A glucocorticoid–FAS axis controls immune evasion during metastatic seeding
肿瘤(癌症)患者之家