PO.CL05.05 · 临床研究
重编程T细胞网络以克服卵巢癌复发中的免疫逃逸
Reprogramming T-cell networks to overcome immune evasion in ovarian cancer relapse
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
卵巢癌（OC）由于其高复发率和对标准疗法的耐药性，仍是一项重大的临床挑战。高级别浆液性卵巢癌（HGSOC）是最常见且最具侵袭性的OC亚型，常表现出肿瘤浸润淋巴细胞（TILs），然而免疫检查点阻断（ICB）疗法的疗效有限。我们的研究旨在解析OC肿瘤微环境（TME）的时空演变，重编程T细胞网络，并开发新一代免疫疗法以恢复抗肿瘤免疫。我们整合了高分辨率空间蛋白质组学、单细胞转录组学和计算建模，以绘制原发、复发和治疗耐药OC中TIL动态的图谱。我们采用了临床前模型，包括OC复发的同基因BRCA1突变型和野生型小鼠模型，以研究OC复发期间肿瘤内在和TME驱动的免疫抑制机制。我们利用数字病理多重免疫荧光（mIF）对来自五个独立队列的697例卵巢癌（OC）标本进行分类，提供了迄今最广泛的基于CD8+ T细胞的免疫图谱分析。我们的预测算法基于TIL浸润和空间组织，识别出OC中不同的肿瘤免疫表型（即纯炎症型、混合炎症型、排斥型和荒漠型），这些表型与HRD状态相关并可预测治疗结局。我们观察到这些肿瘤免疫表型之间以及它们在疾病复发过程中的动态存在显著的免疫和分子异质性。炎症型HRD肿瘤在化疗后维持了T细胞-髓系细胞生态位。在临床前模型中，这与基因组重排的恢复相关。复发的小鼠HRD肿瘤上调了免疫抑制性PGE2-EP2/4通路，在化疗期间靶向COX驱动的PGE2生成可在临床前小鼠模型中显著延长复发时间和生存期，确定了人HRD OC复发的一个关键脆弱点。相比之下，同源重组修复功能完整型（HRP）OC肿瘤演变为T细胞排斥型或荒漠型表型，其特征为恶性细胞过表达Nduf4l2/半乳糖凝集素，以及Trem2/ApoE过度活跃的肿瘤相关巨噬细胞（TAMs）。我们的数据提示，在治疗上靶向TREM2过表达的TAMs可能改善抗肿瘤免疫应答，并延迟HRP OC一线化疗后的复发。通过揭示驱动复发OC免疫逃逸的细胞和分子网络，我们的发现为精准免疫治疗提供了路线图。我们的工作凸显了新型免疫生物标志物和治疗靶点，可用于重新调校抗肿瘤T细胞应答，为复发OC及其他免疫耐药性恶性肿瘤的临床可操作策略铺平道路。
查看英文原文 English abstract
Ovarian cancer (OC) remains a major clinical challenge due to its high recurrence rates and resistance to standard therapies. High-grade serous ovarian cancer (HGSOC), the most common and aggressive OC subtype, often presents with tumor-infiltrating lymphocytes (TILs), yet immune checkpoint blockade (ICB) therapies have shown limited efficacy. Our studies aim to dissect the spatiotemporal evolution of the OC tumor microenvironment (TME), reprogram T cell networks, and develop next-generation immunotherapies to restore anti-tumor immunity. We integrated high-resolution spatial proteomics, single-cell transcriptomics, and computational modeling to map TIL dynamics across primary, recurrent, and treatment-resistant OC. Preclinical models, including syngeneic BRCA1-mutant and wild-type mouse models of OC recurrence, are employed to investigate tumor-intrinsic and TME-driven mechanisms of immune suppression during OC relapse. We utilized digital pathology multiplex immunofluorescence (mIF) to classify 697 ovarian cancer (OC) specimens from five independent cohorts, offering the most extensive CD8+ T cell-based immune profiling to date. Our predictive algorithm identified distinct tumor immune phenotypes in OC (i.e. purely inflamed, mixed inflamed, excluded, and desert) based on TIL infiltration and spatial organization, which correlate with HRD status and predict therapeutic outcomes. We observed significant immune and molecular heterogeneity between these tumor immune phenotypes and their dynamics during disease recurrence. Inflamed HRD tumors, maintained T cell-myeloid niches post-chemotherapy. In preclinical models, this was associated with restoration of genomic rearrangements. Recurrent murine HRD tumors upregulated the immunosuppressive PGE2-EP2/4 pathway and targeting of COX-driven PGE2 production during chemotherapy significantly prolonged relapse and survival in preclinical mouse models, identifying a key vulnerability for the recurrence of human HRD OCs. In contrast, homologous recombination repair proficient (HRP) OC tumors evolved into T-cell excluded or desert phenotypes, characterized by malignant cells overexpressing Nduf4l2/Galectins and Trem2/ApoE overactive tumor-associated macrophages (TAMs). Our data suggest that therapeutically targeting of TREM2 overexpressing TAMs may improve anti-tumor immune responses and delay recurrence after first-line chemotherapy in HRP OC. By unraveling the cellular and molecular networks driving immune evasion in recurrent OC, our findings provide a roadmap for precision immunotherapy. Our work highlights novel immune biomarkers and therapeutic targets that can be exploited to retune anti-tumor T cell responses, paving the way for clinically actionable strategies in recurrent OC and other immune-resistant malignancies.
利益披露 Disclosure
D. Dangaj Laniti, None.