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

Abstract

Summary 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.

Novel immune signatures associated with dysplastic naevi and primary cutaneous melanoma in human skin

“…In accordance with the increased immunosuppressive landscape in melanoma, our study identified increased DCs expressing suppressive markers that have previously been associated with tolerogenic, immunoregulatory function. Similar to SOCS2, which was previously identified as a protein expressed by dendritic cells that is critical for limiting antitumor immune response in MM, SOCS3 is also a member of the suppressor of cytokine signalling (SOCS) proteins family. SOCS3 expression by dendritic cells has not previously been described in human melanoma.…”

Memory T cell subsets in healthy gingiva and periodontitis tissues

“…The role of IFN‐γ in maintaining immune homeostasis is less well described. A recent study suggests that IFN‐γ regulates homeostasis in healthy tissue by upregulation of suppressor‐of‐cytokine‐2 (SOCS2) protein expressed by tissue phagocytes . Moreover, we previously described that IFN‐γ induces indoleamine 2, 3‐dioxygenase production from gingival fibroblast cells .…”

Interferon gamma in cancer immunotherapy

“…IFNγ could induce expression of suppressor‐of‐cytokine‐2 (SOCS2) protein, a conserved program transcript, which is expressed by mononuclear phagocytes infiltrating primary melanoma. SOCS2 limits adaptive antitumor immunity and DC‐based priming of T cells in vivo . These results link immune homeostasis to key determinants of antitumor immunity and escape, uncovering the underlying mechanism by which IFNγ contributes to tumor escape in the tumor microenvironments.…”