Understanding and reversing mammary tumour-driven reprogramming of myelopoieisis to reduce metastatic spread [ATAC-seq]

Tumour-induced systemic accumulation and polarisation of neutrophils to an immunosuppressive phenotype is a potent driver of metastasis formation. Yet how mammary tumours reprogram granulopoiesis at the molecular level and when tumour imprinting occurs during neutrophil development remains underexplored. Here we combined single cell, chromatin and functional analyses to unravel the tumour-driven reprogramming of granulopoiesis, along with intervention studies aimed at reversing this process. We observe that mammary tumours accelerate commitment to the neutrophil lineage at the expense of lymphopoiesis and erythropoiesis without stimulating the development of a novel myeloid lineage. Moreover, tumour-directed immunosuppressive imprinting of neutrophils starts early in haematopoiesis. Treatment with anti-IL-1β normalised tumour-induced granulopoiesis, reduced neutrophil production of T cell suppressive superoxides and mitigated metastatic spread. Together, these data provide molecular insights into the aberrant tumour-driven neutrophil differentiation pathway leading to metastasis-promoting chronic inflammation and how it can be reversed to reduce metastatic spread.