Role of IFN-lambda in Promoting Breast Cancer Metastasis

远处转移是大约90%的乳腺癌(BC)死亡的原因。在BC期间 在发展过程中，转移的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细胞参与其中 来控制肿瘤的发展。然而，在转移过程中，肿瘤细胞可能会损害 NK细胞靶向和逃避NK细胞控制的机制。因此，朝着识别免疫相关的方向 与BC侵袭性相关的因素，我们分析了人类BC样本的微阵列数据库和 建立了BC细胞系。我们特别关注干扰素(干扰素)相关的转录产物，因为 I型干扰素对抗癌反应的影响。重要的是，我们观察到干扰素-lambda的表达 (干扰素-λ)受体1(IFNLR1)是新发现的III型干扰素-λ的唯一受体，与 ER表达阳性。此外，我们还发现，在干扰素-λ反应中， 原发和转移的肿瘤细胞。具体而言，与缺少IFNLR1的原代肿瘤细胞相比 转移细胞表达IFNLR1后，通过信号转导通路1的激活检测，对干扰素-λ有反应。 用干扰素-λ体外培养转移的BC细胞可加速体内转移。此外，在鼠标中 在转移性BC细胞中，我们发现干扰素-λ下调NK细胞激活受体NKG2D的配体H60， 并使BC对NK细胞裂解产生抵抗。我们的初步数据表明，IFNLR1表达的诱导 在BC细胞上与促进远端转移有关，这对BC患者来说是致命的，因为 缺乏有效的治疗方法。我们的数据还表明，内源性干扰素-λ的独立增加可能会助长BC 散开。我们推测，除了抑制NK细胞肿瘤杀伤外，BC细胞中的干扰素-λ信号可能 诱导肿瘤迁移和侵袭。干扰素-λ诱导NKG2D配体下调并可能发生转移 对NK细胞介导的杀伤有抵抗性的BC细胞。检测IFNLR1信号在体内对远端细胞的影响 转移，我们建议建立具有不同IFNLR1表达的小鼠和人BC细胞系 在免疫活性小鼠肿瘤模型和免疫重组人体内监测其转移潜能 异种移植瘤模型。我们还建议检查基因消融IFNLR1对体内远端的影响 同种异体IFNLR1-/-MMTV-PYMT小鼠的肿瘤转移及其体内沉默 免疫重组患者来源异种移植模型。确定分子机制(S) 在干扰素-λ介导的NKG2D配体下调的基础上，我们计划研究干扰素-λ对NKG2D配体的影响。 通过miRNA抑制NKG2D配体基因表达或通过激活NKG2D配体脱落 基质金属蛋白酶。我们认为，研究干扰素-λ/IFNLR轴的作用对于 开发针对转移性结直肠癌的新靶向疗法。

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.