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Nat Commun. 2019 Sep 3;10(1):3974. doi: 10.1038/s41467-019-11911-5.

Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers.

Author information

1
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
2
Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, 98195, USA.
3
Comparative Pathology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
4
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
5
Alvord Brain Tumor Center, University of Washington, Seattle, WA, 98195, USA.
6
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. mstephan@fredhutch.org.
7
Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA, 98105, USA. mstephan@fredhutch.org.
8
Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, 98195, USA. mstephan@fredhutch.org.

Abstract

Tumor-associated macrophages (TAMs) usually express an M2 phenotype, which enables them to perform immunosuppressive and tumor-promoting functions. Reprogramming these TAMs toward an M1 phenotype could thwart their pro-cancer activities and unleash anti-tumor immunity, but efforts to accomplish this are nonspecific and elicit systemic inflammation. Here we describe a targeted nanocarrier that can deliver in vitro-transcribed mRNA encoding M1-polarizing transcription factors to reprogram TAMs without causing systemic toxicity. We demonstrate in models of ovarian cancer, melanoma, and glioblastoma that infusions of nanoparticles formulated with mRNAs encoding interferon regulatory factor 5 in combination with its activating kinase IKKβ reverse the immunosuppressive, tumor-supporting state of TAMs and reprogram them to a phenotype that induces anti-tumor immunity and promotes tumor regression. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this immunotherapy could enable physicians to obviate suppressive tumors while avoiding systemic treatments that disrupt immune homeostasis.

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