PARP-inhibition reprograms macrophages toward an anti-tumor phenotype

• Published in: Cell reports (Cambridge) Vol. 41; no. 2; p. 111462
• Main Authors: Wang, Lin, Wang, Dan, Sonzogni, Olmo, Ke, Shizhong, Wang, Qi, Thavamani, Abhishek, Batalini, Felipe, Stopka, Sylwia A., Regan, Michael S., Vandal, Steven, Tian, Shengya, Pinto, Jocelin, Cyr, Andrew M., Bret-Mounet, Vanessa C., Baquer, Gerard, Eikesdal, Hans P., Yuan, Min, Asara, John M., Heng, Yujing J., Bai, Peter, Agar, Nathalie Y.R., Wulf, Gerburg M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-10-2022
• Subjects: Adenosine Diphosphate; CD47 Antigen; Cell Line, Tumor; Macrophages; NAD; Niacinamide; PARP-inhibitor; Phenotype; Phthalazines - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Reactive Oxygen Species; tumor immunology; tumor metabolism; NAD; macrophages; tumor immunology; PARP-inhibitor; CP: Cancer; tumor metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111462

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.
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•PARP inhibition reprograms metabolism and transcription in macrophages•Accumulation of NAD increases reactive oxygen species via reverse electron transport•High ROS production and phagocytic capacity result in anti-tumor function•The combination of olaparib with CD47 antibodies improves outcomes in a mouse model
Wang et al. demonstrate that a PARP inhibitor used to treat breast tumors with homologous recombination (HR) deficiency reprograms the HR-proficient macrophages in the tumor microenvironment toward an anti-tumor phenotype. Blocking the “don’t-eat-me” signal on tumor cells with anti-CD47 antibodies enhances the therapeutic efficacy of olaparib in a mouse model.