PTEN缺失塑造高等级浆液性卵巢癌中的巨噬细胞动态

PTEN Loss Shapes Macrophage Dynamics in High-Grade Serous Ovarian Carcinoma

CANCER RESEARCH

影响因子:16.6

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

DOI: 10.1158/0008-5472.CAN-23-3890

摘要

高等级浆液性卵巢癌（HGSC）仍是一种预后不良、对现有免疫检查点抑制剂无反应的疾病。尽管PI3K通路的改变（如PTEN缺失）在HGSC中较为常见，但针对该通路的治疗尝试未获成功。我们假设异常的PI3K通路激活可能改变HGSC的免疫微环境，并提供靶向机会。单细胞RNA测序鉴定了特异性存在于PTEN缺失的肠膜肿瘤中的常驻巨噬细胞亚群，这一结果通过流式细胞术得到验证。这些巨噬细胞来源于腹腔液巨噬细胞，表现出独特的基因表达程序，主要特征是高表达酶血红素氧合酶-1（HMOX1）。靶向常驻腹腔巨噬细胞可阻止HMOX1高表达巨噬细胞的出现，并减少肿瘤生长。此外，直接抑制HMOX1在体内延长生存期。RNA测序发现，Pten-缺失的肿瘤细胞中的IL33很可能是驱动因素，促使HMOX1高表达巨噬细胞的出现。人类HGSC肿瘤也含有HMOX1高表达巨噬细胞，并表现出相应的基因表达谱。此外，这些巨噬细胞的存在与肿瘤PI3K/mTOR信号通路激活及患者预后不良相关。相反，具有较少HMOX1高表达巨噬细胞的肿瘤，表现出增强的适应性免疫反应基因表达。这些数据提示，靶向HMOX1高表达巨噬细胞可能成为治疗预后不良HGSC的潜在策略。意义：HMOX1高表达的巨噬细胞在PTEN缺失的高等级浆液性卵巢癌中富集，促进肿瘤生长，具有潜在的治疗靶点价值。

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.