2. Academic Validation
  3. Dynamic immunoediting by macrophages in homologous recombination deficiency-stratified pancreatic ductal adenocarcinoma

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.
Wei-Feng Hong 1,  Feng Zhang 2,  Nan Wang 3,  Jun-Ming Bi 4,  Ding-Wen Zhang 2,  Lu-Sheng Wei 2,  Zhen-Tao Song 5,  Gordon B Mills 6,  Min-Min Chen 7,  Xue-Xin Li 8,  Shi-Suo Du 9,  Min Yu 10
Affiliations

Affiliations

  • 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: xuexin.li@ki.se.
  • 9 Department of Radiation Oncology, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: du.shisuo@zs-hospital.sh.cn.
  • 10 Department of Pancreas Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China. Electronic address: yumin@gdph.org.cn.
PMID: 39002266 DOI: 10.1016/j.drup.2024.101115
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.

Keywords

Homologous recombination deficiency; Macrophage; Pancreatic ductal adenocarcinoma; Spatial phenotypic-transcriptomic profiling; Targeted therapy.

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