LAUSR

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-infiltrating neutrophils, defined as tumor-associated neutrophil progenitors (NePs). These NePs are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity.  Mechanistically, succinate secreted by tumor-associated NePs inhibits homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire  genomic instability, resulting in tumor progression and resistance to endocrine therapies.  Selective inhibition of these pathways induces increased tumor cell kill in vitro  and  in vivo. Intra-tumor NePs score correlates  with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumorigenic effect of these neutrophils and reverses endocrine resistance. Citation Format: Arianna Calcinotto. Tumor-infiltrating neutrophil progenitors impair homologous DNA repair and promote sensitivity to PARP-inhibition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5956.