PARP-inhibition reprograms macrophages toward an anti-tumor phenotype
Lin Wang, Dan Wang, Olmo Sonzogni, Shizhong Ke, Qi Wang, Abhishek Thavamani, Felipe Batalini, Sylwia A Stopka, Michael S Regan, Steven Vandal, Shengya Tian, Jocelin Pinto, Andrew M Cyr, Vanessa C Bret-Mounet, Gerard Baquer, Hans P Eikesdal, Min Yuan, John M Asara, Yujing J Heng, Peter Bai, Nathalie Y R Agar, Gerburg M Wulf, Lin Wang, Dan Wang, Olmo Sonzogni, Shizhong Ke, Qi Wang, Abhishek Thavamani, Felipe Batalini, Sylwia A Stopka, Michael S Regan, Steven Vandal, Shengya Tian, Jocelin Pinto, Andrew M Cyr, Vanessa C Bret-Mounet, Gerard Baquer, Hans P Eikesdal, Min Yuan, John M Asara, Yujing J Heng, Peter Bai, Nathalie Y R Agar, Gerburg M Wulf
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.
Trial registration: ClinicalTrials.gov NCT02624973.
Keywords: CP: Cancer; NAD+; PARP-inhibitor; macrophages; tumor immunology; tumor metabolism.
Conflict of interest statement
Declaration of interests N.Y.R.A. is key opinion leader for Bruker Daltonics, scientific advisor to Invicro, and receives support from Thermo Finnegan and EMD Serono. H.P.E. reports personal fees (honoraria, consulting, or advisory role) from Amgen, AstraZeneca, Abbvie, Bristol-Myers-Squibb, Daiichi Sankyo, Dagens Medisin, Eli Lilly, HAI Interaktiv AS, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, and Seagen. G.M.W. reports grants from Merck & Co. and institutional support from Glaxo Smith Kline outside the submitted work. In addition, G.M.W. has US patent 20090258352 A1 Pin1 as a marker for abnormal cell growth licensed to Cell Signaling, R&D Systems. O.S. is a 2seventy bio employee and obtains compensation and has equity in the company. H.P.E. received institutional funding from AstraZeneca (ESR-14-10077) and Pfizer (GMGS 51752519).
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
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