Role of IFN-lambda in Promoting Breast Cancer Metastasis

IFN-lambda 在促进乳腺癌转移中的作用

• 批准号: 9494987
• 负责人: Ahmed Lasfar
• 金额: $ 36.37万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2018-10-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9494987
• 关键词: 4T1; Ablation; Adoption; Autologous; Binding; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; Breast Cancer therapy; Breast cancer metastasis; Cancer Burden; Cancer Patient; Cause of Death; Cell surface; Cells; Cessation of life; Clinic; Clinical; Cytolysis; Data; Databases; Detection; Development; Disease; Distal; Distant Metastasis; Down-Regulation; Estrogen Receptors; Estrogen receptor negative; Future; Gelatinase B; Gene Expression; Genes; Genetic; Growth; Human; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunotherapy; In Vitro; Inbred BALB C Mice; Infiltration; Interferon Type I; Interferons; Ligands; Malignant Neoplasms; Matrix Metalloproteinases; Measures; Mediating; Membrane Proteins; Messenger RNA; Metastatic breast cancer; MicroRNAs; Microarray Analysis; Modeling; Molecular; Monitor; Mouse Mammary Tumor Virus; Mus; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Neoplasm Transplantation; Operative Surgical Procedures; Patients; Positioning Attribute; Primary Neoplasm; Property; Public Health; Receptor Activation; Research; Resistance; Role; STAT1 gene; Signal Transduction; Specimen; System; Tissues; Transcript; Visceral metastasis; Woman; Xenograft Model; Xenograft procedure; anti-cancer; base; cancer therapy; cytotoxicity; immune reconstitution; improved; in vivo; in vivo evaluation; malignant breast neoplasm; migration; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; peripheral blood; prevent; protein expression; receptor; receptor expression; response; tumor; tumor xenograft

Distant metastases are the cause of approximately 90% of deaths due to breast cancer (BC). During BC development, novel properties are acquired by metastatic BC cells, allowing them to spread and escape immune system control. Recent studies on patients with early BC strongly suggest the involvement of NK cells in the control of tumor development. However, during metastasis, tumor cells may compromise the mechanisms of NK cell targeting and escape NK cell control. Therefore, towards identifying immune-related factors associated with BC aggressiveness, we analyzed microarray databases of human BC specimens and established BC cell lines. We specifically focused on interferon (IFN)-related transcripts due to the important impact of type I IFNs on anti-cancer responses. Importantly, we observed that the expression of IFN-lambda (IFN-λ) receptor 1 (IFNLR1), the unique receptor for the newly discovered type III INF-λ, negatively correlates with ER expression. Furthermore, we discovered a significant difference in the IFN-λ response between primary and metastatic tumor cells. Specifically, in contrast to primary tumor cells, which lack IFNLR1 expression, metastatic cells express IFNLR1 and are responsive to IFN-λ, as measured by STAT1 activation. Ex vivo culture of metastatic BC cells with IFN-λ leads to accelerated in vivo metastasis. In addition, in mouse metastatic BC cells, we found that IFN-λ down-regulates H60, a ligand for NK cell activation receptor NKG2D, and renders BC resistant to NK cell lysis. Our preliminary data indicate that the induction of IFNLR1 expression on BC cells is associated with the promotion of distal metastasis, which is fatal for BC patients due to a current lack of efficient therapy. Our data also indicate that an independent increase in endogenous IFN-λ may fuel BC spread. We hypothesize that in addition to inhibiting NK cell tumor killing, IFN-λ signaling in BC cells may induce tumor migration and invasion. IFN-λ-induces NKG2D ligand down regulation and may afford metastatic BC cells with resistance to NK cell-mediated killing. To test the in vivo impact of IFNLR1 signaling on distal metastasis, we propose to generate murine and human BC cell lines with differential IFNLR1 expression and monitor their metastatic potential in immune competent mouse tumor models and immune-reconstituted human xenograft tumor models. We also propose to examine the impact of genetic ablation of IFNLR1 on in vivo distal tumor metastasis in syngeneic IFNLR1-/- MMTV-PyMT mice and in vivo silencing of IFNLR1 in our autologous immune-reconstituted patient-derived xenograft (AIR-PDX) model. To determine the molecular mechanism(s) underlying IFN-λ-mediated downregulation of NKG2D ligands, we plan to investigate the effect of IFN-λ on the inhibition of NKG2D ligand gene expression via miRNA or shedding of NKG2D ligands through the activation of matrix metalloproteinases. We believe that investigating the role of the IFN-λ/IFNLR axis is crucial for developing new targeted therapies against metastatic BC.

远处转移是大约90%的乳腺癌（BC）死亡的原因。BC期间 在发展过程中，转移性BC细胞获得了新的特性，使它们能够扩散和逃逸， 免疫系统控制。最近对早期BC患者的研究强烈表明NK细胞的参与 控制肿瘤的发展。然而，在转移过程中，肿瘤细胞可能会损害肿瘤细胞的功能。 NK细胞靶向和逃避NK细胞控制的机制。因此，为了识别免疫相关的 与BC侵袭性相关的因素，我们分析了人类BC标本的微阵列数据库， 建立BC细胞系。我们特别关注干扰素（IFN）相关的转录本，因为重要的是 I型干扰素对抗癌反应的影响。重要的是，我们观察到IFN-λ的表达 (IFN-λ）受体1（IFNLR 1），新发现的III型INF-λ的独特受体， ER表达。此外，我们发现IFN-λ反应在以下两种情况之间存在显著差异： 原发性和转移性肿瘤细胞。具体地说，与缺乏IFNLR 1的原发性肿瘤细胞相反， 在IFN-γ表达的情况下，转移性细胞表达IFNLR 1并响应于IFN-λ，如通过STAT 1活化所测量的。 转移性BC细胞与IFN-λ的离体培养导致加速的体内转移。此外，在小鼠 在转移性BC细胞中，我们发现IFN-λ下调H60，一种NK细胞活化受体NKG 2D的配体， 并使BC对NK细胞裂解具有抗性。我们的初步数据表明，诱导IFNLR 1的表达， 与促进远端转移有关，这对于BC患者来说是致命的， 缺乏有效的治疗。我们的数据还表明，内源性IFN-λ的独立增加可能会助长BC 传播.我们推测，除了抑制NK细胞杀伤肿瘤外，BC细胞中的IFN-λ信号可能 诱导肿瘤迁移和侵袭。IFN-λ-诱导NKG 2D配体下调，可能导致转移性 对NK细胞介导的杀伤具有抗性的BC细胞。为了测试IFNLR 1信号传导对远端细胞的体内影响， 转移，我们建议产生具有差异IFNLR 1表达的鼠和人BC细胞系， 监测它们在免疫活性小鼠肿瘤模型和免疫重建的人肿瘤模型中的转移潜力。 异种移植肿瘤模型。我们还建议研究基因消融IFNLR 1对体内远端细胞的影响。 在同基因IFNLR 1-/- MMTV-PyMT小鼠中的肿瘤转移和在我们的自体肿瘤细胞中IFNLR 1的体内沉默， 免疫重建患者来源异种移植物（AIR-PDX）模型。确定分子机制 作为IFN-λ介导的NKG 2D配体下调的基础，我们计划研究IFN-λ对NKG 2D配体的影响。 通过miRNA抑制NKG 2D配体基因表达或通过激活NKG 2D配体脱落 基质金属蛋白酶。我们认为，研究IFN-λ/IFNLR轴的作用对于 开发针对转移性BC的新靶向疗法。