Editors' ChoiceCancer

Interferon with antitumor immunity

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Science Translational Medicine  26 Jul 2017:
Vol. 9, Issue 400, eaao0976
DOI: 10.1126/scitranslmed.aao0976

Abstract

IFN-γ directs homeostatic differentiation of tissue APCs but may subvert aspects of tumor immune surveillance.

Professional antigen presenting cells (APCs) function as immune sentinels in peripheral tissues. While ever alert to foreign threats, they are also peacekeepers that maintain tolerance to self-antigens. How tissue APCs acquire and execute this critical homeostatic function remains a mystery with relevance to autoimmunity and cancer.

Nirschl et al. elegantly tackle this question using bioinformatic and functional analyses of pathways involved in programming of skin APCs during health and malignancy. Probing published datasets, they found that 227 genes previously determined to define the genetic signature of skin dendritic cells (DCs) are also enriched in murine and human tissue macrophages and monocytes, suggesting broad conservation of this homeostatic APC differentiation program. Testing for overlap between the DC genetic signature and those in hundreds of other transcriptome datasets, including 200 of human skin disease, identified interferon-γ (IFN-γ) as a key conditioning cue for expression of the differentiation program, which was in turn down-regulated in murine DCs lacking the IFN-γ receptor. Thus, IFN-γ appears to drive programming of the tissue APC signature in healthy skin.

But does this program influence immunity against cancer? Nirschl et al. found that skin DC and IFN-γ–associated gene signatures were enriched across 30 human malignancies and induced in primary melanoma, suggesting preservation and accentuation of IFN-γ–induced gene regulation in the tumor microenvironment. Notably, SOCS2, which encodes suppressor of cytokine signaling 2, was one of the signature genes increased in melanoma. DC-specific deletion of SOCS2 dramatically increased tumor-specific T cell priming and reduced tumor growth in mouse models. These finding implicate SOCS2 as a key player in the IFN-γ–dependent homeostatic APC program that normally helps the immune system remain balanced but is co-opted by tumors, undermining antitumoral immunity.

Together this work indicates that a previously undefined, broadly conserved, and IFN-γ–directed program is critical to APC differentiation and their role in immune homeostasis. Although certain genes, such as SOCS2, may subvert tumor immune surveillance, enrichment of the APC signature positively correlated with survival of melanoma patients, indicating that this program ultimately promotes antitumor immunity. Future work defining the full spectrum of pathways modulated by IFN-γ–directed APC programming holds great promise for elucidating therapeutic targets for cancer immunotherapy or treatment of autoimmunity.

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