Department of Pancreas Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China; Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou 310005, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310005, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou 310005, China.
Department of Pancreas Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
Drug Resist Updat. 2024 Sep;76:101115. doi: 10.1016/j.drup.2024.101115. Epub 2024 Jul 6.
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.
胰腺导管腺癌（PDAC）是一种致命的疾病，对现有疗法具有明显的耐药性。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 中的效果并不理想，并且在充分了解 HRD 相关 PDAC 的独特特征和影响方面仍存在重大挑战。我们分析了 16 个 PDAC 患者来源的组织，根据其同源重组缺陷（HRD）评分进行分类，并进行了高通量免疫荧光分析以定义 20 种细胞表型，从而生成原位 PDAC 肿瘤免疫景观。通过感兴趣区域（ROI）进行的空间表型转录组分析确定了一种关键的调节机制，该机制可能通过局部肿瘤相邻巨噬细胞以 HRD 依赖的方式发挥作用。细胞邻域（CN）分析进一步证明了在空间背景下存在与巨噬细胞相关的高阶细胞功能单元。我们使用多组学空间分析策略，揭示了一种动态的巨噬细胞介导的调节轴，将 HRD 状态与 SIGLEC10 和 CD52 联系起来。这些发现表明，针对 CD52 联合 PARPi 作为 PDAC 的治疗干预具有潜力。
