The CLARINET trial led to the approval of lanreotide for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (NETs). It is hypothesized that lanreotide regulates proliferation, hormone synthesis, and other cellular functions via binding to somatostatin receptors (SSTR1–5) present in NETs. However, our knowledge of how lanreotide affects the immune system is limited. In vitro studies have investigated functional immune response parameters with lanreotide treatment in healthy donor T cell subsets, encompassing the breadth of SSTR expression, apoptosis induction, cytokine production, and activity of transcription factor signaling pathways. In our study, we characterized in vitro immune mechanisms in healthy donor T cells in response to lanreotide. We also studied the in vivo effects by looking at differential gene expression pre- and post-lanreotide therapy in patients with NET. Immune-focused gene and protein expression profiling was performed on peripheral blood samples from 17 NET patients and correlated with clinical response. In vivo, lanreotide therapy showed reduced effects on wnt, T cell receptor (TCR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling in CD8+ T cells in responders compared to non-responders. Compared to non-responders, responders showed reduced effects on cytokine and chemokine signaling but greater effects on ubiquitination and proteasome degradation genes. Our results suggest significant lanreotide pharmacodynamic effects on immune function in vivo, which correlate with responses in NET patients. This is not evident from experimental in vitro settings.
CLARINET试验促使兰瑞肽获批用于治疗胃肠胰神经内分泌肿瘤（NET）患者。据推测，兰瑞肽通过结合NET中存在的生长抑素受体（SSTR1-5）来调节增殖、激素合成和其他细胞功能。然而，我们对兰瑞肽如何影响免疫系统的了解有限。体外研究已探讨了兰瑞肽治疗对健康供体T细胞亚群的功能性免疫反应参数，涵盖了SSTR表达范围、凋亡诱导、细胞因子产生以及转录因子信号通路活性。在我们的研究中，我们描述了健康供体T细胞对兰瑞肽的体外免疫机制。我们还通过观察NET患者兰瑞肽治疗前后的差异基因表达，研究了其体内效应。对17名NET患者的外周血样本进行了以免疫为重点的基因和蛋白质表达谱分析，并将其与临床反应相关联。在体内，与无应答者相比，应答者中兰瑞肽治疗对CD8+ T细胞中wnt、T细胞受体（TCR）和核因子κB（NF-kB）信号通路的影响减弱。与无应答者相比，应答者中细胞因子和趋化因子信号通路的影响减弱，但对泛素化和蛋白酶体降解基因的影响更大。我们的结果表明，兰瑞肽在体内对免疫功能具有显著的药效学效应，这与NET患者的反应相关。这在实验性体外环境中并不明显。
肿瘤(癌症)患者之家