Ovarian Cancer Immunotherapy Using PD-L1 siRNA Targeted Delivery from Folic Acid-Functionalized Polyethylenimine: Strategies to Enhance T Cell Killing
Pei Yun Teo
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore, 138669 Singapore
Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
Search for more papers by this authorChuan Yang
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore, 138669 Singapore
Search for more papers by this authorLynsey M. Whilding
Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
King's College London, Guy's Hospital, St Thomas Street, London, SE1 9RT UK
Search for more papers by this authorAna C. Parente-Pereira
King's College London, Guy's Hospital, St Thomas Street, London, SE1 9RT UK
Search for more papers by this authorJohn Maher
King's College London, Guy's Hospital, St Thomas Street, London, SE1 9RT UK
Search for more papers by this authorAndrew J. T. George
Brunel University, Kingston Lane, Uxbridge, Middlesex, UB8 3PH UK
Search for more papers by this authorJames L. Hedrick
IBM Almaden Research Center, 650 Harry Road, San Jose, CA, 95120 USA
Search for more papers by this authorCorresponding Author
Yi Yan Yang
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore, 138669 Singapore
E-mail: [email protected], [email protected]Search for more papers by this authorCorresponding Author
Sadaf Ghaem-Maghami
Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
E-mail: [email protected], [email protected]Search for more papers by this authorPei Yun Teo
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore, 138669 Singapore
Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
Search for more papers by this authorChuan Yang
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore, 138669 Singapore
Search for more papers by this authorLynsey M. Whilding
Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
King's College London, Guy's Hospital, St Thomas Street, London, SE1 9RT UK
Search for more papers by this authorAna C. Parente-Pereira
King's College London, Guy's Hospital, St Thomas Street, London, SE1 9RT UK
Search for more papers by this authorJohn Maher
King's College London, Guy's Hospital, St Thomas Street, London, SE1 9RT UK
Search for more papers by this authorAndrew J. T. George
Brunel University, Kingston Lane, Uxbridge, Middlesex, UB8 3PH UK
Search for more papers by this authorJames L. Hedrick
IBM Almaden Research Center, 650 Harry Road, San Jose, CA, 95120 USA
Search for more papers by this authorCorresponding Author
Yi Yan Yang
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore, 138669 Singapore
E-mail: [email protected], [email protected]Search for more papers by this authorCorresponding Author
Sadaf Ghaem-Maghami
Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
E-mail: [email protected], [email protected]Search for more papers by this authorAbstract
Adoptive T cell immunotherapy is a promising treatment strategy for epithelial ovarian cancer (EOC). However, programmed death ligand-1 (PD-L1), highly expressed on EOC cells, interacts with programmed death-1 (PD-1), expressed on T cells, causing immunosuppression. This study aims to block PD-1/PD-L1 interactions by delivering PD-L1 siRNA, using various folic acid (FA)–functionalized polyethylenimine (PEI) polymers, to SKOV-3-Luc EOC cells, and investigate the sensitization of the EOC cells to T cell killing. To enhance siRNA uptake into EOC cells, which over express folate receptors, PEI is modified with FA or PEG–FA so that siRNA is complexed into nanoparticles with folate molecules on the surface. PEI modification with a single functional group lowers the polymer cytotoxicity compared to unmodified PEI. FA-conjugated polymers increase siRNA uptake into SKOV-3-luc cells and decrease unspecific uptake into monocytes. All polymers result in 40% to 50% PD-L1 protein knockdown. Importantly, SKOV-3-Luc cells treated with either PEI–FA or PEI– polyethylene glycol (PEG)–FA/PD-L1 siRNA complexes are up to twofold more sensitive to T cell killing compared to scrambled siRNA treated controls. These findings are the first to demonstrate that PD-L1 knockdown in EOC cells, via siRNA/FA-targeted delivery, are able to sensitize cancer cells to T cell killing.
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