PO.IM01.04 · 免疫学
内皮抑素与催乳素联合触发PRLR诱导并在TNBC中引导CD1d信号传导
Endostatin and prolactin combination trigger PRLR induction and channelize CD1d signaling in TNBC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
三阴性乳腺癌（TNBC）是一种极具侵袭性的乳腺癌亚型，由于缺乏激素受体（ER、PR和HER2）而在治疗上具有挑战性。TCGA数据集显示，催乳素受体（PRLR）在TNBC中下调，与较差的总生存期相关。PRLR诱导已被证明可减少TNBC的肿瘤增殖。然而，尚无报道能够诱导PRLR的药理活性分子。此外，自然杀伤T（NKT）细胞是通过CD1d脂质抗原相互作用激活的强效抗肿瘤免疫细胞，在TNBC肿瘤中减少。先前的研究表明，CD1d表达对乳腺肿瘤的进展至关重要，并调节由NKT细胞活化介导的抗肿瘤免疫应答。在本研究中，我们发现用内皮抑素（2.5 μM，一种抗血管生成蛋白）联合催乳素（2.5 nM）处理显著降低了TNBC细胞的增殖和集落形成能力。发现该联合处理在TNBC细胞系MDA-MB-468中诱导PRLR和CD1d表达（CD1d A和B亚型）。此外，我们观察到该联合处理降低了上皮-间质转化（EMT）标志物和氧化磷酸化标志物COXIV。从PBMC中分离人NKT细胞并与经处理的TNBC细胞共培养。通过ELISA量化IFN-gamma分泌以测定NKT活化。使用TNBC组织切片进行的额外分析正在进行中，以确定PRLR和CD1d的共表达模式。我们的发现将内皮抑素介导的PRLR恢复确定为一种限制TNBC细胞生长同时增强CD1d依赖性NKT细胞活化的新策略，代表了TNBC一种有前景的治疗选择。
查看英文原文 English abstract
Triple-negative breast cancer (TNBC) is a very aggressive breast cancer subtype and therapeutically challenging because of the absence of hormone receptors (ER, PR and HER2). TCGA datasets revealed that prolactin receptor (PRLR) was downregulated in TNBC, associated with poor overall survival. PRLR induction has been shown to reduce tumor proliferation in TNBC. However, no pharmacologically active molecule has been reported that can induce PRLR. In addition, natural killer T (NKT) cells, potent antitumorigenic immune cells activated via CD1d lipid antigen interactions, are diminished in TNBC tumors. Prior studies have demonstrated that CD1d expression is crucial for the progression of breast tumors and regulates antitumor immune responses mediated by NKT cell activation. In this study, we found that treating endostatin (2.5 μM), an anti-angiogenic protein, in combination with prolactin (2.5 nM) significantly reduced the proliferation and colony-forming potential of TNBC cells. The treatment combination was found to induce PRLR and CD1d expression (CD1d A and B isoforms) in the TNBC cell line MDA-MB-468. Further, we observed that the combination reduced epithelial-mesenchymal transition (EMT) markers and oxidative phosphorylation marker COXIV. Human NKT cells were isolated from PBMCs and co-cultured with treated TNBC cells. NKT activation was quantified by IFN-gamma secretion using ELISA. Additional analyses using TNBC tissue slides are undergoing to determine PRLR and CD1d co-expression patterns. Our findings identify endostatin-mediated restoration of the PRLR as a novel strategy to restrict TNBC cell growth while simultaneously enhancing CD1d-dependent NKT cell activation, representing a promising therapeutic option for TNBC.
利益披露 Disclosure
R. Shyanti, None..
R. Singh, None..
M. Mishra, None.