To tease apart the balance between tolerance and immunity, Nirschl et al. examined an IFNγ-inducible 227 gene signature enriched in tissue-resident and migratory DCs that positively correlates with metastatic melanoma survival. One of the key induced transcripts (SOCS2) suppresses adaptive immune response, preserving tissue homeostasis, but potentially allowing tumor growth.
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. IFNgamma is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNgamma-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 IFNgamma. 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.