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IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment
Christopher J. Nirschl, Mayte Suárez-Fariñas, Benjamin Izar, Sanjay Prakadan, Ruth Dannenfelser, Itay Tirosh, Yong Liu, Qian Zhu, K. Sanjana P. Devi, Shaina L. Carroll, David Chau, Melika Rezaee, Tae Gyun Kim, Ruiqi Huang, Judilyn Fuentes-Duculan, George X. Song-Zhao, Nicholas Gulati, Michelle A. Lowes, Sandra L. King, Francisco J. Quintana, Young suk Lee, James G. Krueger, Kavita Y. Sarin, Charles H. Yoon, Levi Garraway, Aviv Regev, Alex K. Shalek, Olga Troyanskaya, Niroshana Anandasabapathy
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.