Abstract：
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.
摘要：
胰腺导管腺癌（PDAC）是一种致命的疾病，特别是对现有疗法有抵抗力。目前的研究表明，缺乏同源重组（HR）的PDAC患者受益于基于铂的治疗和聚ADP-核糖聚合酶抑制剂（PARPi）。然而,PARPi在HR缺陷(HRD)PDAC中的有效性是次优的，在充分理解与HRD相关的PDAC的独特特征和含义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）评分分类，并进行了高复合免疫荧光分析以定义20种细胞表型，从而产生原位PDAC肿瘤免疫景观。由感兴趣区域（ROI）指导的空间表型-转录组分析通过局部肿瘤相邻巨噬细胞确定了一个关键的调节机制，可能以依赖HRD的方式。细胞邻域（CN）分析进一步证明了在空间环境中存在与巨噬细胞相关的高阶细胞功能单元。使用我们的多组学空间分析策略，我们发现了将HRD状态与SIGLEC10和CD52连接的动态巨噬细胞介导的调节轴.这些发现证明了靶向CD52与PARPi组合作为PDAC治疗干预的潜力。
