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National Institute of Environmental Health Sciences

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Publication Detail

Title: IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment.

Authors: Nirschl, Christopher J; Suárez-Fariñas, Mayte; Izar, Benjamin; Prakadan, Sanjay; Dannenfelser, Ruth; Tirosh, Itay; Liu, Yong; Zhu, Qian; Devi, K Sanjana P; Carroll, Shaina L; Chau, David; Rezaee, Melika; Kim, Tae-Gyun; Huang, Ruiqi; Fuentes-Duculan, Judilyn; Song-Zhao, George X; Gulati, Nicholas; Lowes, Michelle A; King, Sandra L; Quintana, Francisco J; Lee, Young-Suk; Krueger, James G; Sarin, Kavita Y; Yoon, Charles H; Garraway, Levi; Regev, Aviv; Shalek, Alex K; Troyanskaya, Olga; Anandasabapathy, Niroshana

Published In Cell, (2017 Jun 29)

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.

PubMed ID: 28666115 Exiting the NIEHS site

MeSH Terms: Animals; Cell Differentiation; Dendritic Cells/immunology; Homeostasis; Humans; Interferon-gamma/immunology*; Melanoma/genetics; Melanoma/immunology*; Melanoma/pathology; Mice; Monocytes/immunology*; Monocytes/pathology; Neoplasm Metastasis/pathology*; Sequence Analysis, RNA; Single-Cell Analysis; Skin Neoplasms/genetics; Skin Neoplasms/immunology*; Skin Neoplasms/pathology; Suppressor of Cytokine Signaling Proteins/metabolism*; Transcriptome; Tumor Microenvironment*

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