Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer
Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer
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DOI：
10.1038/s41467-020-17644-0
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发表时间：
2020-07-30
影响因子：
16.6
通讯作者：
Galluzzi, Lorenzo
中科院分区：
文献类型：
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作者：
Buque, Aitziber;Bloy, Norma;Galluzzi, Lorenzo
激素受体 (HR)(+) 乳腺癌 (BC) 导致大多数 BC 相关死亡，因此需要改进治疗方法。尽管有预期，但免疫检查点阻断剂 (ICB) 在 HR+ BC 患者中的活性较差，部分原因是缺乏能够概括免疫功能正常宿主疾病进展的临床前模型。我们证明，由醋酸甲羟孕酮 (M) 和 7,12-二甲基苯并[a]蒽 (D) 驱动的乳腺肿瘤概括了人腔 B HR(+)HER2(-) BC 的几个关键特征，包括有限的免疫浸润和对 ICB 的敏感性差。免疫缺陷加速了 M/D 驱动的肿瘤发生，表明 M/D 驱动的肿瘤处于免疫监视之下。安全的营养措施，包括补充烟酰胺 (NAM)，可通过重新激活免疫监视有效延迟 M/D 驱动的肿瘤发生。 NAM 还介导针对已建立的 M/D 驱动和可移植 BC 的免疫治疗作用，这在很大程度上反映了恶性细胞 I 型干扰素分泌的增加和免疫效应细胞的直接刺激。我们的研究结果表明 NAM 是预防和治疗 HR+ BC 的潜在策略。目前用于研究人类 HR+乳腺癌进展和体内免疫治疗反应的临床前模型是有限的。在这里，作者证明，由合成孕激素与口服致癌物结合驱动的乳腺肿瘤概括了人类 HR+ 乳腺癌的几个免疫生物学特征。
Hormone receptor (HR)(+) breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR(+)HER2(-) BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC. Current preclinical models to investigate human HR+breast cancer progression and response to immunotherapy in vivo are limited. Here, the authors demonstrate that mammary tumours driven by a synthetic progestin combined with an oral carcinogen recapitulate several immunobiological features of human HR+breast cancers.