Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Malay Haldar

Abstract

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.

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Available to all on Friday, January 31, 2025

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