Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [RNA-seq]

Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutical opportunities. Here, we identified a novel subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in female highly proliferative hormone-dependent breast cancers and impair DNA repair capacity.? Mechanistically, succinate secreted by tumor-associated PreNeu inhibit homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire?genomic instability promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro?and?in vivo. Tumor-associated PreNeu score correlates?with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumoral effect of these neutrophils. Overall design: MCF-7 cells, plated in EMEM medium supplemented with 10% heat- inactivated charcoal-stripped FBS (CS-FBS), were treated with either conditioned medium (CM) obtained from PreNeu (cm-PreNeu;), from LOX-1+ neutrophils (cm-LOX1), or control (Ø).