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

Cell. 2017 Jun 29;170(1):127-141.e15. doi: 10.1016/j.cell.2017.06.016.


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.

Keywords: IFNγ; dendritic cells; differentiation; homeostasis; immunotherapy; melanoma; suppressor-of-cytokine-signaling 2 (SOCS2); tissue mononuclear phagocytes; tolerance; tumor microenvironment.

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*


  • IFNG protein, human
  • SOCS2 protein, human
  • Suppressor of Cytokine Signaling Proteins
  • Interferon-gamma