IFNγ is a Central Node of Cancer Immune Equilibrium.

Michael J. Walsh,Courtney T. Stump,Rakeeb Kureshi,Patrick Lenehan,Lestat R. Ali,Michael Dougan,David M. Knipe,Stephanie K. Dougan

Cell Reports（2023）SCI 4区

Harvard Med Sch | Dana Farber Canc Inst | Massachusetts Gen Hosp

Cited 7|Views30

Abstract

Tumors in immune equilibrium are held in balance between outgrowth and destruction by the immune system. The equilibrium phase defines the duration of clinical remission and stable disease, and escape from equilibrium remains a major clinical problem. Using a non-replicating HSV-1 vector expressing interleukin-12 (d106S-IL12), we developed a mouse model of therapy-induced immune equilibrium, a phenomenon previously seen only in humans. This immune equilibrium was centrally reliant on interferon-γ (IFNγ). CD8+ T cell direct recognition of MHC class I, perforin/granzyme-mediated cytotoxicity, and extrinsic death receptor signaling such as Fas/FasL were all individually dispensable for equilibrium. IFNγ was critically important and played redundant roles in host and tumor cells such that IFNγ sensing in either compartment was sufficient for immune equilibrium. We propose that these redundant mechanisms of action are integrated by IFNγ to protect from oncogenic or chronic viral threats and establish IFNγ as a central node in therapy-induced immune equilibrium.

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Key words

IFNγ,equilibrium,virus,IL-12,cytokine,melanoma,checkpoint blockade resistance,virotherapy,MHC I deficiency,b2m loss

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