Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-11911-5
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Funding
- FHCRC Immunotherapy Initiative
- Bezos Family Foundation
- Experimental Histopathology Shared Resource of the Fred Hutchinson/University of Washington Cancer Consortium [P30 CA015704]
- National Science Foundation [1452492, 1644363]
- American Cancer Society [RSG-16-110-01-LIB]
- American Brain Tumor Association (ABTA)
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [1644363, 1452492] Funding Source: National Science Foundation
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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 IKK beta 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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