RT Journal Article
SR Electronic
T1 ATM-mediated DNA damage response in macrophages primes phagocytosis and immune checkpoint regulation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.14.987438
DO 10.1101/2020.03.14.987438
A1 Aakanksha Bansal
A1 René Neuhaus
A1 Elena Izquierdo-Alvarez
A1 Daniela Vorholt
A1 Henning Feldkötter
A1 Hendrik Nolte
A1 Philipp Lohneis
A1 Reinhard Büttner
A1 Markus Krüger
A1 Christian P. Pallasch
A1 Björn Schumacher
YR 2020
UL http://biorxiv.org/content/early/2020/03/15/2020.03.14.987438.abstract
AB Genotoxin-based cancer therapies trigger a DNA damage response (DDR) to eliminate cancer cells but similarly exert profound alterations to the immune cell compartment. Macrophages in the tumor microenvironment are important and multifaceted components in actively sustaining tumor progression but also in clearance of tumor cells and play an important role in the outcome of chemotherapy. Here, we report that post neo-adjuvant chemotherapy macrophages in tumor samples display elevated expression of the immune checkpoint PD-L1. We determined that chemotherapy or direct application of DNA damage to macrophages in vitro triggers a specific MDDR polarization phenotype characterized by increased phagocytic activity, elevated PD-L1 expression, and induction of endotoxin tolerance. Phospho-proteomics analysis revealed epigenetic alterations and ATM-dependent induction of senescence in macrophages upon DNA damage. We propose that ATM-induced senescence and PD-L1 immune checkpoint induction mediate a specific MDDR macrophage polarization that might contribute to chemotherapy responses. Furthermore, our results clarify the functional role of tumor associated macrophages in the context of DNA damage and combination therapies including checkpoint inhibition.