TitleIFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment.
Publication TypeJournal Article
Year of Publication2017
AuthorsNirschl, CJ, Suárez-Fariñas, M, Izar, B, Prakadan, S, Dannenfelser, R, Tirosh, I, Liu, Y, Zhu, Q, K Devi, SP, Carroll, SL, Chau, D, Rezaee, M, Kim, T-G, Huang, R, Fuentes-Duculan, J, Song-Zhao, GX, Gulati, N, Lowes, MA, King, SL, Quintana, FJ, Lee, Y-suk, Krueger, JG, Sarin, KY, Yoon, CH, Garraway, L, Regev, iv, A, Shalek, AK, Troyanskaya, OG, Anandasabapathy, N
Date Published2017 Jun 29
KeywordsAnimals, Cell Differentiation, Dendritic Cells, Homeostasis, Humans, Interferon-gamma, Melanoma, Mice, Monocytes, Neoplasm Metastasis, Sequence Analysis, RNA, Single-Cell Analysis, Skin Neoplasms, Suppressor of Cytokine Signaling Proteins, Transcriptome, 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 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.

Alternate JournalCell
PubMed ID28666115
PubMed Central IDPMC5569303
Grant ListT32 AR007098 / AR / NIAMS NIH HHS / United States
K23 AR063461 / AR / NIAMS NIH HHS / United States
DP2 GM119419 / GM / NIGMS NIH HHS / United States
R01 AR070234 / AR / NIAMS NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States