Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Nat Commun. 2024 Oct 1;15(1):8514. doi: 10.1038/s41467-024-52553-6.
Tumor immune microenvironment (TIME) spatial organization predicts outcome and therapy response in triple-negative breast cancer (TNBC). An immunosuppressive TIME containing elevated tumor-associated macrophages (TAM) and scarce CD8+ T cells is associated with poor outcome, but the regulatory mechanisms are poorly understood. Here we show that ETS1-driven caspase-1 expression, required for IL1β processing and TAM recruitment, is negatively regulated by estrogen receptors alpha (ERα) and a defining feature of TNBC. Elevated tumoral caspase-1 is associated with a distinct TIME characterized by increased pro-tumoral TAMs and CD8+ T cell exclusion from tumor nests. Mouse models prove the functional importance of ERα, ETS1, caspase-1 and IL1β in TIME conformation. Caspase-1 inhibition induces an immunoreactive TIME and reverses resistance to immune checkpoint blockade, identifying a therapeutically targetable mechanism that governs TNBC spatial organization.
肿瘤免疫微环境（TIME）的空间组织预测三阴性乳腺癌（TNBC）的结局和治疗反应。富含肿瘤相关巨噬细胞（TAM）和稀少 CD8+T 细胞的免疫抑制性 TIME 与不良预后相关，但调控机制尚不清楚。在这里，我们表明，ETS1 驱动的半胱氨酸蛋白酶 1 表达是 IL1β 加工和 TAM 募集所必需的，受雌激素受体 α（ERα）的负调控，是 TNBC 的一个特征。肿瘤中 caspase-1 的升高与一种独特的 TIME 相关，其特征是促肿瘤 TAM 增加，以及 CD8+T 细胞从肿瘤巢中被排除。小鼠模型证明了 ERα、ETS1、caspase-1 和 IL1β 在 TIME 构象中的功能重要性。Caspase-1 抑制诱导免疫反应性 TIME，并逆转对免疫检查点阻断的耐药性，确定了一种可治疗的靶点机制，该机制控制 TNBC 的空间组织。
