PO.IM01.02 · 免疫学
SECN-15：反义寡核苷酸介导的Neuropilin-1抑制增强抗肿瘤免疫并克服实体瘤中的检查点抑制剂耐药
SECN-15: Antisense oligonucleotide-mediated Neuropilin-1 suppression enhances anti-tumor immunity and overcomes checkpoint inhibitor resistance in solid tumors
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摘要 Abstract
中文摘要
背景：免疫检查点抑制剂（ICIs）已变革了癌症治疗，但由于肿瘤微环境（TME）的抑制性特征，其在许多实体瘤中的疗效仍然有限。Neuropilin-1（NRP1）是一种多功能共受体，通过免疫抑制机制和新生血管生成促进肿瘤进展。高NRP1表达与包括胃癌在内的多种实体瘤的不良预后和ICI耐药相关。SECN-15是一种锁核酸（LNA）修饰的反义寡核苷酸（ASO），旨在选择性下调NRP1并拮抗其促肿瘤功能。
方法：使用OligoCreator™平台生成NRP1特异性ASOs，并在同基因小鼠肿瘤模型中作为单药或与抗PD-(L)1抗体联合进行体外和体内评估。在RNA和蛋白水平评估NRP1敲低，包括作为靶点接合生物标志物的可溶性NRP1。通过流式细胞术和RNA测序分析肿瘤细胞组成和转录组谱。对来自癌症患者的公开可获得的bulk和单细胞RNA-seq数据集进行计算机模拟分析，为即将开展的I/II期临床试验提供适应证选择依据，并阐明NRP1在人类肿瘤中的生物学。
结果：对荷瘤小鼠进行全身性SECN-15治疗诱导了巨噬细胞、T细胞和内皮细胞中NRP1的稳健敲低，无论是作为单药还是与抗PD-1治疗联合，均导致肿瘤生长延迟并在一部分动物中实现完全消退。转录组谱分析揭示促炎通路上调以及细胞外基质和上皮-间质转化（EMT）基因下调。对胃癌患者单细胞RNA-seq数据集的分析鉴定出内皮细胞和巨噬细胞是主要的NRP1表达群体。与NRP1low对应细胞相比，NRP1high内皮细胞表现出TGF-beta信号的激活，而NRP1high巨噬细胞则表现出缺氧和EMT通路的上调以及同种异体移植排斥特征谱的抑制。这些发现提示NRP1在胃癌中促进一种免疫调节性、促血管生成的TME，进一步支持将其选为主导适应证。
结论：SECN-15代表了一种增强抗肿瘤免疫并克服ICI耐药的有前景的治疗策略。临床前和单细胞数据的整合凸显了NRP1在维持免疫抑制性TME中的作用，目前正在体外模型中对此进行进一步研究。IND支持性研究正在进行，以推动SECN-15进入临床开发。
查看英文原文 English abstract
Background:Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, but their efficacy remains limited in many solid tumors due to suppressive features of the tumor microenvironment (TME). Neuropilin-1 (NRP1), a multifunctional co-receptor, promotes tumor progression through immunosuppressive mechanisms and neoangiogenesis. High NRP1 expression correlates with poor prognosis and ICI resistance in different solid tumors, including gastric cancer. SECN-15 is a locked nucleic acid (LNA)-modified antisense oligonucleotide (ASO) designed to selectively downregulate NRP1 and counteract its protumorigenic functions.
Methods: NRP1-specific ASOs were generated using the OligoCreator™ platform and evaluated in vitro and in vivo in syngeneic murine tumor models as monotherapy or in combination with anti-PD-(L)1 antibodies. NRP1 knockdown was assessed at RNA and protein levels, including soluble NRP1 as a target engagement biomarker. Tumor cell composition and transcriptomic profiles were analyzed by flow cytometry and RNA sequencing. In silico analyses of publicly available bulk and single-cell RNA-seq datasets from cancer patients informed indication selection for the upcoming Phase I/II clinical trial and elucidated NRP1 biology in human tumors.
Results: Systemic SECN-15 treatment of tumor-bearing mice induced robust NRP1 knockdown in macrophages, T cells, and endothelial cells, leading to tumor growth delay and complete regressions in a subset of animals, both as monotherapy and in combination with anti-PD-1 treatment. Transcriptomic profiling revealed upregulation of pro-inflammatory pathways and downregulation of extracellular matrix and epithelial-to-mesenchymal transition (EMT) genes. Analysis of single-cell RNA-seq datasets from patients with gastric cancer identified endothelial cells and macrophages as major NRP1-expressing populations. NRP1high endothelial cells exhibited activation of TGF-beta signaling, while NRP1high macrophages showed an upregulation of hypoxia and EMT pathways and suppressed allograft rejection signatures, in comparison with their NRP1low counterparts. These findings suggest that NRP1 promotes an immunoregulatory, pro-angiogenic TME in gastric cancer, further supporting its selection as a lead indication.
Conclusion: SECN-15 represents a promising therapeutic strategy to enhance anti-tumor immunity and overcome ICI resistance. Integration of preclinical and single-cell data highlights NRP1's role in sustaining an immunosuppressive TME which is currently further investigated in in vitro models. IND-enabling studies are underway to advance SECN-15 into clinical development.
利益披露 Disclosure
A. Maaske, None..
S. Michel, None..
A. Sadewasser, None..
J. Festag, None..
M. Schell, None..
J. Sekar, None..
S. Raith, None..
F. Jaschinski, None..
R. Klar, None.