Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, United States of America.
Department of Breast, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China.
PLoS One. 2021 Mar 29;16(3):e0248996. doi: 10.1371/journal.pone.0248996. eCollection 2021.
One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and prevent immune surveillance. One such element associated with breast cancer is stromal fibrosis, a histopathologic criterion for invasive cancer and poor survival. Fibrosis is caused by inflammatory factors and remodeling of the extracellular matrix that elicit an immune tolerant microenvironment. To address the role of fibrosis in tumorigenesis, we developed NeuT/ATTAC transgenic mice expressing a constitutively active NeuT/erbB2 transgene, and an inducible, fat-directed caspase-8 fusion protein, which upon activation results in selective and partial ablation of mammary fat and its replacement with fibrotic tissue. Induction of fibrosis in NeuT/ATTAC mice led to more rapid tumor development and an inflammatory and fibrotic stromal environment. In an effort to explore therapeutic options that could reduce fibrosis and immune tolerance, mice were treated with the oxysterol liver X receptor (LXR) pan agonist, N,N-dimethyl-3-β-hydroxy-cholenamide (DMHCA), an agent known to reduce fibrosis in non-malignant diseases. DMHCA reduced tumor progression, tumor multiplicity and fibrosis, and improved immune surveillance by reducing infiltrating myeloid-derived suppressor cells and increasing CD4 and CD8 effector T cells. These effects were associated with downregulation of an LXR-dependent gene network related to reduced breast cancer survival that included Spp1, S100a9, Anxa1, Mfge8 and Cd14. These findings suggest that the use of DMHCA may be a potentially effective approach to reduce desmoplasia and immune tolerance and increase the efficacy of cancer therapy.
癌症治疗的核心挑战之一是识别肿瘤微环境中的因素，这些因素会增加肿瘤进展并阻止免疫监视。与乳腺癌相关的一个因素是基质纤维化，这是浸润性癌症和不良生存的组织病理学标准。纤维化是由炎症因子和细胞外基质的重塑引起的，这些因子引发了免疫耐受的微环境。为了研究纤维化在肿瘤发生中的作用，我们开发了 NeuT/ATTAC 转基因小鼠，该小鼠表达组成性激活的 NeuT/erbB2 转基因和可诱导的、脂肪定向的半胱天冬酶-8 融合蛋白，该蛋白激活后可选择性和部分消融乳腺脂肪及其纤维化组织。在 NeuT/ATTAC 小鼠中诱导纤维化会导致更快的肿瘤发展以及炎症和纤维化的基质环境。为了探索可能减少纤维化和免疫耐受的治疗选择，我们用氧化固醇肝 X 受体 (LXR) 泛激动剂 N,N-二甲基-3-β-羟基胆酰胺 (DMHCA) 治疗小鼠，该试剂已知可减少非恶性疾病中的纤维化。DMHCA 可降低肿瘤进展、肿瘤多发性和纤维化，并通过减少浸润性髓样来源的抑制细胞和增加 CD4 和 CD8 效应 T 细胞来改善免疫监视。这些作用与 LXR 依赖性基因网络的下调有关，该网络与降低乳腺癌生存率有关，包括 Spp1、S100a9、Anxa1、Mfge8 和 Cd14。这些发现表明，使用 DMHCA 可能是一种潜在有效的方法，可以减少纤维组织增生和免疫耐受，并提高癌症治疗的疗效。
