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PARP-inhibition reprograms macrophages toward an anti-tumor phenotype

Lin Wang1, Dan Wang2, Olmo Sonzogni1

  • 1Cancer Center and Cancer Research Institute, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.

Cell Reports
|October 12, 2022
PubMed

Insights

Poly(ADP)ribosylation inhibitors (PARPis) reprogram tumor-associated macrophages (TAMs) to enhance anti-tumor activity in BRCA1-related breast cancer. Combining PARPis with CD47 blockade further improves treatment outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Poly(ADP)ribosylation inhibitors (PARPis) target cancer cells with homologous recombination (HR) deficiency.
  • Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) have complex roles in cancer progression.
  • The impact of PARP inhibition on TAM function in BRCA1-related breast cancer (BC) remains to be fully elucidated.

Purpose of the Study:

  • To investigate the effects of PARP inhibition on TAMs in the context of BRCA1-related breast cancer.
  • To understand the underlying molecular mechanisms of PARPi-induced TAM reprogramming.
  • To evaluate the therapeutic potential of combining PARPi with immune checkpoint blockade.

Main Methods:

  • Treatment of BRCA1-related BC models with the PARPi olaparib.
  • Analysis of TAM reprogramming, including cytotoxicity and phagocytosis.
  • Metabolic profiling to assess changes in NAD+, glycolysis, and oxidative phosphorylation.
  • Investigation of mitochondrial electron transport and reactive oxygen species (ROS) production.
  • In vivo and ex vivo experiments to assess anti-tumor efficacy.

Main Results:

  • Olaparib treatment reprograms TAMs towards enhanced cytotoxicity and phagocytosis.
  • PARPi-induced metabolic shifts include increased NAD+, heightened glycolysis, and blunted oxidative phosphorylation.
  • Reverse mitochondrial electron transport (RET) and increased ROS are observed, alongside transcriptional reprogramming.
  • These effects occur independently of PARP1 or PARP2 and can be partially mimicked by methyl-nicotinamide (MNA).
  • Olaparib's effect on TAMs contributes significantly to its anti-tumor efficacy.

Conclusions:

  • PARP inhibition actively reprograms TAMs, enhancing their anti-tumor functions in BRCA1-related breast cancer.
  • The observed metabolic and mitochondrial alterations in TAMs are key to this reprogramming.
  • Combination therapy with CD47 blockade and olaparib demonstrates improved outcomes in preclinical models, suggesting a promising therapeutic strategy.
Keywords:
CP: CancerNAD+PARP-inhibitormacrophagestumor immunologytumor metabolism

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