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Immunity. 2019 Sep 17;51(3):548-560.e4. doi: 10.1016/j.immuni.2019.07.003. Epub 2019 Aug 27.

Oncolytic Viruses Engineered to Enforce Leptin Expression Reprogram Tumor-Infiltrating T Cell Metabolism and Promote Tumor Clearance.

Author information

1
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
2
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; School of Medicine, Tsinghua University, Beijing, China.
3
Head and Neck Cancer SPORE, University of Pittsburgh, Pittsburgh, PA, USA.
4
Division of Rheumatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
5
Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
6
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Head and Neck Cancer SPORE, University of Pittsburgh, Pittsburgh, PA, USA.
7
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Head and Neck Cancer SPORE, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: delgoffeg@upmc.edu.

Abstract

Immunotherapy can reinvigorate dormant responses to cancer, but response rates remain low. Oncolytic viruses, which replicate in cancer cells, induce tumor lysis and immune priming, but their immune consequences are unclear. We profiled the infiltrate of aggressive melanomas induced by oncolytic Vaccinia virus using RNA sequencing and found substantial remodeling of the tumor microenvironment, dominated by effector T cell influx. However, responses to oncolytic viruses were incomplete due to metabolic insufficiencies induced by the tumor microenvironment. We identified the adipokine leptin as a potent metabolic reprogramming agent that supported antitumor responses. Leptin metabolically reprogrammed T cells in vitro, and melanoma cells expressing leptin were immunologically controlled in mice. Engineering oncolytic viruses to express leptin in tumor cells induced complete responses in tumor-bearing mice and supported memory development in the tumor infiltrate. Thus, leptin can provide metabolic support to tumor immunity, and oncolytic viruses represent a platform to deliver metabolic therapy.

KEYWORDS:

cancer; immunometabolism; immunotherapy; leptin; memory; oncolytic virus; single cell

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