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 (Mar 2023)

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

Affiliations

Michael J. Walsh: Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Harvard Program in Virology, Boston, MA, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Courtney T. Stump: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA
Rakeeb Kureshi: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA
Patrick Lenehan: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA
Lestat R. Ali: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Michael Dougan: Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
David M. Knipe: Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Stephanie K. Dougan: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 3
p. 112219

Abstract

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Summary: 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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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