IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment.
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Abstract | Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment. |
Year of Publication | 2017
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Journal | Cell
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Volume | 170
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Issue | 1
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Pages | 127-141.e15
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Date Published | 2017 Jun 29
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ISSN | 1097-4172
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DOI | 10.1016/j.cell.2017.06.016
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PubMed ID | 28666115
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PubMed Central ID | PMC5569303
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Grant list | T32 AR007098 / AR / NIAMS NIH HHS / United States
R01 AI126880 / AI / NIAID NIH HHS / United States
K23 AR063461 / AR / NIAMS NIH HHS / United States
DP2 GM119419 / GM / NIGMS NIH HHS / United States
R01 GM071966 / GM / NIGMS NIH HHS / United States
R01 AR070234 / AR / NIAMS NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
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