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Author |
Walters, A.A.; Santacana-Font, G.; Li, J.; Routabi, N.; Qin, Y.; Claes, N.; Bals, S.; Tzu-Wen Wang, J.; Al-Jamal, K.T. |
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Title |
Nanoparticle-MediatedIn SituMolecular Reprogramming of Immune Checkpoint Interactions for Cancer Immunotherapy |
Type |
A1 Journal article |
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Year  |
2021 |
Publication |
Acs Nano |
Abbreviated Journal |
Acs Nano |
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Volume |
15 |
Issue |
11 |
Pages |
17549-17564 |
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Keywords |
A1 Journal article; Pharmacology. Therapy; Engineering sciences. Technology; Electron microscopy for materials research (EMAT) |
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Abstract |
Immune checkpoint blockade involves targeting immune
regulatory molecules with antibodies. Preclinically, complex multiantibody
regimes of both inhibitory and stimulatory targets are a promising
candidate for the next generation of immunotherapy. However, in this
setting, the antibody platform may be limited due to excessive toxicity
caused by off target effects as a result of systemic administration. RNA
can be used as an alternate to antibodies as it can both downregulate
immunosuppressive checkpoints (siRNA) or induce expression of
immunostimulatory checkpoints (mRNA). In this study, we demonstrate
that the combination of both siRNA and mRNA in a single
formulation can simultaneously knockdown and induce expression of
immune checkpoint targets, thereby reprogramming the tumor
microenvironment from immunosuppressive to immunostimulatory
phenotype. To achieve this, RNA constructs were synthesized and
formulated into stable nucleic acid lipid nanoparticles (SNALPs); the SNALPs produced were 140−150 nm in size with >80%
loading efficiency. SNALPs could transfect macrophages and B16F10 cells in vitro resulting in 75% knockdown of inhibitory
checkpoint (PDL1) expression and simultaneously express high levels of stimulatory checkpoint (OX40L) with minimal
toxicity. Intratumoral treatment with the proposed formulation resulted in statistically reduced tumor growth, a greater
density of CD4+ and CD8+ infiltrates in the tumor, and immune activation within tumor-draining lymph nodes. These data
suggest that a single RNA-based formulation can successfully reprogram multiple immune checkpoint interactions on a
cellular level. Such a candidate may be able to replace future immune checkpoint therapeutic regimes composed of both
stimulatory- and inhibitory-receptor-targeting antibodies. |
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Wos |
000747115200039 |
Publication Date |
2021-11-23 |
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Edition |
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ISSN |
1936-0851 |
ISBN |
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Additional Links |
UA library record; WoS full record; WoS citing articles |
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Impact Factor |
13.942 |
Times cited |
11 |
Open Access |
OpenAccess |
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Notes |
A.A.W. is the grateful recipient of a Maplethorpe Fellowship. K.A.J. acknowledges funding from the British Council (Newton Fund, 337313), Wellcome Trust (WT103913), and the Cancer Research UK King’s Health Partners Centre at King’s College London. Financial support is acknowledged from the European Commission under the Horizon 2020 Programme, by means of Grant Agreement No. 731019 (EUSMI). Images were drawn on BioRender.com. |
Approved |
Most recent IF: 13.942 |
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Call Number |
EMAT @ emat @c:irua:183950 |
Serial |
6829 |
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| Permanent link to this record |
