PTEN损失塑造高级浆液卵巢癌中的巨噬细胞动力学
PTEN Loss Shapes Macrophage Dynamics in High-Grade Serous Ovarian Carcinoma
影响因子:16.60000
分区:医学1区 Top / 肿瘤学1区
发表日期:2024 Nov 15
作者:
Sarah Spear, Olivia Le Saux, Hasan B Mirza, Nayana Iyer, Katie Tyson, Fabio Grundland Freile, Josephine B Walton, Chloé Woodman, Sheba Jarvis, Darren P Ennis, Carmen Aguirre Hernandez, Yuewei Xu, Pavlina Spiliopoulou, James D Brenton, Ana P Costa-Pereira, David P Cook, Barbara C Vanderhyden, Hector C Keun, Evangelos Triantafyllou, James N Arnold, Iain A McNeish
摘要
高级浆液卵巢癌（HGSC）仍然是一种预后不良的疾病，对当前的免疫检查点抑制剂无反应。尽管PI3K途径的变化（例如PTEN损失）在HGSC中很常见，但试图靶向该途径的尝试并未成功。我们假设异常的PI3K途径激活可能会改变HGSC免疫微环境并提出目标机会。单细胞RNA测序鉴定出鼠模型中针对Pten-null肿瘤特有的居民巨噬细胞种群，通过流式细胞仪证实了这些巨噬细胞。这些巨噬细胞源自腹膜液巨噬细胞，并表现出独特的基因表达程序，标志着酶血红素氧酶-1的高表达（HMOX1）。靶向居民腹膜巨噬细胞阻止了HMOX1HI巨噬细胞的出现并减少了肿瘤的生长。另外，直接抑制HMOX1在体内扩展生存。 RNA测序在PTEN-NULL肿瘤细胞中鉴定出IL33是可能的候选驱动器，导致HMOX1HI巨噬细胞的出现。人类HGSC肿瘤还包含具有相应基因表达程序的HMOX1HI巨噬细胞。此外，这些巨噬细胞的存在与HGSC患者的活化肿瘤PI3K/mTOR信号传导和总体存活率不佳相关。相比之下，适应性免疫反应基因表达增加了HMOX1HI巨噬细胞数量少的肿瘤。这些数据表明，针对HMOX1HI巨噬细胞是治疗预后不良HGSC的潜在治疗策略。意义：HMOX1表达升高的巨噬细胞富含PTEN缺乏的高级浆液卵巢癌，促进肿瘤生长，并代表潜在的治疗靶点。
Abstract
High-grade serous ovarian carcinoma (HGSC) remains a disease with poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity. Single-cell RNA sequencing identified populations of resident macrophages specific to Pten-null omental tumors in murine models, which were confirmed by flow cytometry. These macrophages were derived from peritoneal fluid macrophages and exhibited a unique gene expression program, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). Targeting resident peritoneal macrophages prevented the appearance of HMOX1hi macrophages and reduced tumor growth. In addition, direct inhibition of HMOX1 extended survival in vivo. RNA sequencing identified IL33 in Pten-null tumor cells as a likely candidate driver, leading to the appearance of HMOX1hi macrophages. Human HGSC tumors also contained HMOX1hi macrophages with a corresponding gene expression program. Moreover, the presence of these macrophages was correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in patients with HGSC. In contrast, tumors with low numbers of HMOX1hi macrophages were marked by increased adaptive immune response gene expression. These data suggest targeting HMOX1hi macrophages as a potential therapeutic strategy for treating poor prognosis HGSC. Significance: Macrophages with elevated HMOX1 expression are enriched in PTEN-deficient high-grade serous ovarian carcinoma, promote tumor growth, and represent a potential therapeutic target.