2. Academic Validation
  3. PARP-inhibition reprograms macrophages toward an anti-tumor phenotype

PARP-inhibition reprograms macrophages toward an anti-tumor phenotype

  • Cell Rep. 2022 Oct 11;41(2):111462. doi: 10.1016/j.celrep.2022.111462.
Lin Wang 1,  Dan Wang 2,  Olmo Sonzogni 1,  Shizhong Ke 1,  Qi Wang 1,  Abhishek Thavamani 1,  Felipe Batalini 1,  Sylwia A Stopka 3,  Michael S Regan 4,  Steven Vandal 1,  Shengya Tian 1,  Jocelin Pinto 1,  Andrew M Cyr 1,  Vanessa C Bret-Mounet 5,  Gerard Baquer 4,  Hans P Eikesdal 6,  Min Yuan 7,  John M Asara 7,  Yujing J Heng 5,  Peter Bai 8,  Nathalie Y R Agar 9,  Gerburg M Wulf 10
Affiliations

Affiliations

  • 1 Cancer Center and Cancer Research Institute, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 2 Cancer Center and Cancer Research Institute, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA; Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 5 Cancer Center and Cancer Research Institute, Beth Israel Deaconess Medical Center and Department of Pathology, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Oncology, Haukeland University Hospital, Bergen, Norway; K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.
  • 7 Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 8 Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary; MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen 4032, Hungary; Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary; MTAMTA-DE Cell Biology and Signaling Research Group ELKH, Debrecen 4032, Hungary; Hungary-DE Cell Biology and Signaling Research Group ELKH, Debrecen 4032, Hungary.
  • 9 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 10 Cancer Center and Cancer Research Institute, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: gwulf@bidmc.harvard.edu.
PMID: 36223740 DOI: 10.1016/j.celrep.2022.111462
Abstract

Poly(ADP)ribosylation inhibitors (PARPis) are toxic to Cancer cells with homologous recombination (HR) deficiency but not to HR-proficient cells in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs). As TAMs can promote or inhibit tumor growth, we set out to examine the effects of PARP inhibition on TAMs in BRCA1-related breast Cancer (BC). The PARPi olaparib causes reprogramming of TAMs toward higher cytotoxicity and phagocytosis. A PARPi-related surge in NAD+ increases glycolysis, blunts Oxidative Phosphorylation, and induces reverse mitochondrial electron transport (RET) with an increase in Reactive Oxygen Species (ROS) and transcriptional reprogramming. This reprogramming occurs in the absence or presence of PARP1 or PARP2 and is partially recapitulated by addition of NAD derivative methyl-nicotinamide (MNA). In vivo and ex vivo, the effect of olaparib on TAMs contributes to the anti-tumor efficacy of the PARPi. In vivo blockade of the "don't-eat-me signal" with CD47 Antibodies in combination with olaparib improves outcomes in a BRCA1-related BC model.

Keywords

CP: Cancer; NAD+; PARP-inhibitor; macrophages; tumor immunology; tumor metabolism.

Figures
Products