Dynamic immunoediting by macrophages in homologous recombination deficiency-stratified pancreatic ductal adenocarcinoma

Drug Resist Updat. 2024 Sep:76:101115. doi: 10.1016/j.drup.2024.101115. Epub 2024 Jul 6.

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.

Publication types

  • Review

MeSH terms

  • Carcinoma, Pancreatic Ductal* / drug therapy
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / immunology
  • Carcinoma, Pancreatic Ductal* / pathology
  • Homologous Recombination*
  • Humans
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / immunology
  • Pancreatic Neoplasms* / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Tumor Microenvironment / immunology

Substances

  • Poly(ADP-ribose) Polymerase Inhibitors