Trajectories of macrophage ontogeny and reprogramming in cancer
Summary: Tumor-associated macrophages (TAMs) often manifest immunosuppressive and tumor-promoting phenotypes contributing to immunotherapy resistance. Dicer1 inactivation in TAMs (DKO) prompts their immunostimulatory activation, enabling effective immunotherapy in mouse cancer models. Single-cell RN...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-05-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422500759X |
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| Summary: | Summary: Tumor-associated macrophages (TAMs) often manifest immunosuppressive and tumor-promoting phenotypes contributing to immunotherapy resistance. Dicer1 inactivation in TAMs (DKO) prompts their immunostimulatory activation, enabling effective immunotherapy in mouse cancer models. Single-cell RNA sequencing (scRNA-seq) analysis revealed interferon-γ (IFNγ)-dependent immunostimulatory programming of the tumor microenvironment in DKO mice. In tumors of wild-type mice and patients with cancer, dynamic inferences on macrophage ontogeny by pseudotime analysis identified trajectories associated with monocyte-to-macrophage differentiation, progression into the cell cycle, and transition from immunostimulatory (M1-like) to immunosuppressive and protumoral (M2-like) states. Dicer1 inactivation interfered with this trajectory and stalled TAMs at an intermediate state, impeding immunosuppressive and M2-like TAM development. This reprogramming translated into enhanced response to antiangiogenic immunotherapy in an orthotopic lung cancer model. Cycling/M2-like macrophages are conserved in mouse and human cancers and are enriched in patients with poor response to immunotherapy, making them a more selective therapeutic target than the bulk of TAMs. |
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| ISSN: | 2589-0042 |