Ischemic injury induces hematopoietic aging and facilitates tumor growth [scRNA-seq]

Background: Cancer patients are at increased risk of cardiovascular disease (CVD). In turn, myocardial infarction can accelerate cancer progression in mice and humans. Many mechanisms driving CVD-cancer communication remain poorly understood, including the impact of ischemic injury on cancer development. Objectives: To evaluate breast cancer growth and anti-tumoral immunity following peripheral ischemic insult in mice. Methods: Hind limb ischemia (HLI) by femoral artery ligation or sham surgery was performed on C57BL/6J mice three days after orthotopic implantation of E0771 mammary cancer cells and tumor growth was monitored. Immune cell composition in tumors, circulation, and the bone marrow was assessed by flow cytometry. The influence of ischemia on chromatin accessibility and gene expression in hematopoietic stem and progenitor cells (HSPC) was evaluated by single cell (sc)ATAC- and (sc)RNA-seq. Bone marrow transplant from HLI or sham mice was performed to assess altered responsiveness of HSPCs and their myeloid progeny in restricting tumor growth. Results: Peripheral ischemia accelerated breast cancer growth and increased the accumulation of immunosuppressive regulatory T cells and myeloid cells within tumors. Ischemia also increased monocyte and neutrophil output from the bone marrow at the expense of lymphocytes. Multiomic analyses revealed an increase in myeloid-biased bone marrow HSPCs and a gene signature consistent with inflammation (NLRP3 inflammasome) and aging (Neogenin-1, Thrombospondin-1). This HLI-induced phenotype, including accelerated tumor growth and myeloid-skewing, was transmissible by bone marrow transplantation to naïve recipients, indicating long-term reprogramming of innate immune responses. Conclusions: Peripheral ischemia promotes inflammaging of hematopoietic stem cells and long-lasting alterations to anti-tumoral immunity to accelerate breast tumor growth.