IFNγ-Dependent Tissue-Immune Homeostasis is Co-opted in the Tumor Microenvironment

Cancer Cancer
Genomics Genomics
Immunology Immunology
Alex K. Shalek Alex K. Shalek
Jay Prakadan Jay Prakadan

Nirschl et al.▾ Nirschl, C.J., Suarez-Farinas, M., Izar, B., Prakadan, S., Dannenfelser, R., Tirosh, I., Liu, Y., Zhu, Q., Devi., K.S.P., Carroll, S.L., Chau, D., Rezaee, M., Kim, T., Huang, R., Fuentes-Duculan, J., Song-Zhao, G.X., Gulati, N., Lowes, M.A., King, S.L., Quintana, F.J., Lee, Y., Krueger, J.G., Sarin, K.Y., Yoon, C.H., Garraway, L., Regev, A., Shalek, A.K., Troyanskaya, O., Anandasabapathy, N.


June, 2017


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.