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

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 stead...

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Bibliographic Details
Published in:Cell 2017-06, Vol.170 (1), p.127-141.e15
Main 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
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation
dendritic cells
Dendritic Cells - immunology
differentiation
Homeostasis
Humans
IFNγ
immunotherapy
Interferon-gamma - immunology
melanoma
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
suppressor-of-cytokine-signaling 2 (SOCS2)
tissue mononuclear phagocytes
tolerance
Transcriptome
Tumor Microenvironment
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Summary: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. [Display omitted] •Immune phagocytes share a conserved program during differentiation and tissue entry•IFNγ is a critical instructive cue in the steady state•IFNγ and tissue programming are co-opted across cancers and include SOCS2•SOCS2 is a critical determinant of tumor-immune surveillance in dendritic cells Tumors exploit physiological mechanisms that are in place to keep tissue homeostasis in order to escape the surveillance of the immune system.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2017.06.016