Dynamic immunoediting by macrophages in homologous recombination deficiency-stratified pancreatic ductal adenocarcinoma
- Drug Resist Updat. 2024 Jul 6:76:101115. doi: 10.1016/j.drup.2024.101115.
- 1. 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.
- 2. Department of Pancreas Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
- 3. Cosmos Wisdom Biotech, co. ltd, Building 10, No. 617 Jiner Road, Hangzhou, Zhejiang, China.
- 4. Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
- 5. Mills Institute for Personalized Cancer Care, Fynn Biotechnologies Ltd. Jinan, Shandong, China.
- 6. Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, USA.
- 7. Shenzhen Bay Laboratory, Shenzhen, Guangdong, China.
- 8. Department of Physiology and Pharmacology, Karolinska Institutet, Solna 17165, Sweden. Electronic address: [email protected].
- 9. Department of Radiation Oncology, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: [email protected].
- 10. Department of Pancreas Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China. Electronic address: [email protected].
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.