IFN?-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment. Cell Nirschl, C. J., Suárez-Fariñas, M. n., Izar, B. n., Prakadan, S. n., Dannenfelser, R. n., Tirosh, I. n., Liu, Y. n., Zhu, Q. n., Devi, K. S., Carroll, S. L., Chau, D. n., Rezaee, M. n., Kim, T. G., Huang, R. n., Fuentes-Duculan, J. n., Song-Zhao, G. X., Gulati, N. n., Lowes, M. A., King, S. L., Quintana, F. J., Lee, Y. S., Krueger, J. G., Sarin, K. Y., Yoon, C. H., Garraway, L. n., Regev, A. n., Shalek, A. K., Troyanskaya, O. n., Anandasabapathy, N. n. 2017; 170 (1): 127–41.e15


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.

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