Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [ChIP-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: ChIP-Seq of the histone modification H3K9me3 in MCF-7 cells subjected to CS-FBS and Succinate 2mM (Cat. S9512, Sigma-Aldrich) or control.