Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, notably resistant to existing therapies. Current research indicates that PDAC patients deficient in homologous recombination (HR) benefit from platinum-based treatments and poly-ADP-ribose polymerase inhibitors (PARPi). However, the effectiveness of PARPi in HR-deficient (HRD) PDAC is suboptimal, and significant challenges remain in fully understanding the distinct characteristics and implications of HRD-associated PDAC. We analyzed 16 PDAC patient-derived tissues, categorized by their homologous recombination deficiency (HRD) scores, and performed high-plex immunofluorescence analysis to define 20 cell phenotypes, thereby generating an in-situ PDAC tumor-immune landscape. Spatial phenotypic-transcriptomic profiling guided by regions-of-interest (ROIs) identified a crucial regulatory mechanism through localized tumor-adjacent macrophages, potentially in an HRD-dependent manner. Cellular neighborhood (CN) analysis further demonstrated the existence of macrophage-associated high-ordered cellular functional units in spatial contexts. Using our multi-omics spatial profiling strategy, we uncovered a dynamic macrophage-mediated regulatory axis linking HRD status with SIGLEC10 and CD52. These findings demonstrate the potential of targeting CD52 in combination with PARPi as a therapeutic intervention for PDAC.

中文翻译：

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同源重组缺陷分层胰腺导管腺癌中巨噬细胞的动态免疫编辑


胰腺导管腺癌（PDAC）是一种致命疾病，尤其对现有疗法具有耐药性。目前的研究表明，同源重组 (HR) 缺陷的 PDAC 患者受益于铂类治疗和聚 ADP 核糖聚合酶抑制剂 (PARPi)。然而，PARPi 在 HR 缺陷 (HRD) PDAC 中的有效性并不理想，并且在充分理解 HRD 相关 PDAC 的独特特征和影响方面仍然存在重大挑战。我们分析了 16 个 PDAC 患者来源的组织，按同源重组缺陷 (HRD) 评分进行分类，并进行了高强度免疫荧光分析来定义 20 种细胞表型，从而生成原位 PDAC 肿瘤免疫景观。由感兴趣区域 (ROI) 引导的空间表型转录组分析通过局部肿瘤邻近巨噬细胞确定了一个关键的调节机制，可能以 HRD 依赖性方式进行。细胞邻域（CN）分析进一步证明了空间环境中巨噬细胞相关的高阶细胞功能单元的存在。利用我们的多组学空间分析策略，我们发现了一个动态巨噬细胞介导的调节轴，将 HRD 状态与 SIGLEC10 和 CD52 连接起来。这些发现证明了靶向 CD52 与 PARPi 联合作为 PDAC 治疗干预的潜力。