Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Tumors frequently hemorrhage due to abnormal vasculature. Macrophages phagocytose extravasated erythrocytes to degrade heme, but the impact of hemorrhage and erythrophagocytosis on macrophage-mediated anti-tumor immunity is unknown. We show that intratumoral hemorrhage is associated with a limited anti-tumor immune response and poor survival in human sarcomas. Using multiple mouse models, human tumors, and single-cell transcriptomics, we identify two populations of heme-degrading iron-rich tumor-associated macrophages and isolate these cells using their ferromagnetic properties. Iron-rich TAMs (iTAMs) display immunosuppressive and pro-angiogenic gene signatures, and expresses the endothelin receptor type B (Ednrb). Deletion of Ednrb in myeloid cells reduces tumor growth and vascular density. Mechanistic studies show that heme-mediated degradation of the transcription factor Bach1 drives both Ednrb expression and the global transcriptional program in iTAMs, which is countered by the pro-inflammatory cytokine interferon-gamma. These findings reveal how intratumoral hemorrhage alters macrophage states to promote tumor growth, and identifies macrophage endothelin signaling as a potential target for immunotherapy.
Folkert, Ian Wesley, "Intratumoral Hemorrhage Inhibits Bach1 To Induce Ednrb-Expressing Iron-Rich Macrophages That Promote Tumor Growth" (2021). Publicly Accessible Penn Dissertations. 4853.