IFN?-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment.

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. IFN? is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFN?-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 IFN?. 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.

SUBMITTER: Nirschl CJ 

PROVIDER: S-EPMC5569303 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature