背景:垂体神经内分泌肿瘤(PitNETs)是表现出独特转录因子的常见腺体肿瘤。尽管免疫细胞在PitNETs中的作用已被广泛认可,精确的免疫环境及其对肿瘤细胞的控制知之甚少。
方法:异质性,空间分布,使用单细胞RNA测序(scRNA-seq)分析PitNETs中巨噬细胞的临床意义,批量RNA-seq,空间转录组学,免疫组织化学,和多重定量免疫荧光(QIF)。细胞活力,细胞凋亡测定,体内皮下移植实验证实INHBA-ACVR1B影响肿瘤细胞凋亡的过程。
结果:本研究评估了来自分为3个主要谱系的23个PitNET样品的scRNA-seq数据。目的是探索肿瘤的多样性和这些谱系中免疫细胞的组成。来自内部进行的scRNA-seq和365批量RNA测序样品的分析数据揭示了PitNET中存在三种独特的肿瘤免疫微环境(TIME)亚型。这些亚型的特点是不同程度的免疫浸润,从低到中到高。此外,NR5A1谱系主要与以有限的免疫细胞浸润为特征的亚型相关。表达CX3CR1+的肿瘤相关巨噬细胞(TAMs),C1Q+,GPNMB+与表达NR5A1+的肿瘤细胞接触增强,TBX19+,和POU1F1+,分别。这强调了TAM和肿瘤细胞之间基于其谱系的不同相互作用轴。此外,CX3CR1+巨噬细胞与肿瘤细胞通过INHBA-ACVR1B连接调节肿瘤细胞凋亡。
结论:总之,TIME的不同亚型以及TAM与肿瘤细胞之间的相互作用为影响PitNET发展的TIME控制提供了有价值的见解。这些发现可以用作治疗性干预的预期目标。
Pituitary neuroendocrine tumors (PitNETs) are common gland neoplasms demonstrating distinctive transcription factors. Although the role of immune cells in PitNETs has been widely recognized, the precise immunological environment and its control over tumor cells are poorly understood.
The heterogeneity, spatial distribution, and clinical significance of macrophages in PitNETs were analyzed using single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, spatial transcriptomics, immunohistochemistry, and multiplexed quantitative immunofluorescence (QIF). Cell viability, cell apoptosis assays, and in vivo subcutaneous xenograft experiments have confirmed that INHBA-ACVR1B influences the process of tumor cell apoptosis.
The present study evaluated scRNA-seq data from 23 PitNET samples categorized into 3 primary lineages. The objective was to explore the diversity of tumors and the composition of immune cells across these lineages. Analyzed data from scRNA-seq and 365 bulk RNA sequencing samples conducted in-house revealed the presence of three unique subtypes of tumor immune microenvironment (TIME) in PitNETs. These subtypes were characterized by varying levels of immune infiltration, ranging from low to intermediate to high. In addition, the NR5A1 lineage is primarily associated with the subtype characterized by limited infiltration of immune cells. Tumor-associated macrophages (TAMs) expressing CX3CR1+, C1Q+, and GPNMB+ showed enhanced contact with tumor cells expressing NR5A1 + , TBX19+, and POU1F1+, respectively. This emphasizes the distinct interaction axes between TAMs and tumor cells based on their lineage. Moreover, the connection between CX3CR1+ macrophages and tumor cells via INHBA-ACVR1B regulates tumor cell apoptosis.
In summary, the different subtypes of TIME and the interaction between TAM and tumor cells offer valuable insights into the control of TIME that affects the development of PitNET. These findings can be utilized as prospective targets for therapeutic interventions.