IFN-gamma-dependent tissue immune homeostasis is co-opted in the tumor microenvironment

Homeostatic programs maintain equilibrium between immune protection, and selftolerance. Such mechanisms impact autoimmunity and tumor formation, respectively. How tissue homeostasis is maintained, and impacts tumor surveillance is unknown. Here we identify that mononuclear phagocytes share conserved programming during homeostatic differentiation, and entry into tissue. IFN is necessary and sufficient to induce these transcripts, revealing a key instructive role. Remarkably, homeostatic and IFN-dependent programs enrich across primary human tumors, including melanoma, and stratify metastatic melanoma survival. Single-cell RNA-sequencing reveals enrichment of these modules in monocytes and DCs in human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2), a highly conserved transcript in this program is induced by IFN, and expressed in mononuclear phagocytes infiltrating primary melanoma. SOCS2 limits DC adaptive anti-tumoral immunity and T cell priming in vivo, indicating a critical regulatory role. Our findings link homeostasis in peripheral tissue to anti-tumoral immunity and escape, revealing coopting of tissue-specific immune development in the tumor microenvironment.

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Nirschl CJ, Suárez-Fariñas M, Izar B, Prakadan S, Dannenfelser R, Tirosh I, Liu Y, Zhu Q, Devi KSP, Carroll SL, Chau D, Rezaee M, Kim TG, Huang R, Fuentes-Duculan J, Song-Zhao GX, Gulati N, Lowes MA, King SL, Quintana FJ, Lee YS, Krueger JG, Sarin KY, Yoon CH, Garraway L, Regev A, Shalek AK, Troyanskaya O, Anandasabapathy N