Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer

Xinjian Liu, Xuhui Bao, Mengjie Hu, Hanman Chang, Meng Jiao, Jin Cheng, Liyi Xie, Qian Huang, Fang Li and Chuan-Yuan Li ()
Additional contact information
Xinjian Liu: Duke University Medical Center
Xuhui Bao: Duke University Medical Center
Mengjie Hu: Duke University Medical Center
Hanman Chang: Duke University Medical Center
Meng Jiao: Duke University Medical Center
Jin Cheng: Shanghai Jiaotong University School of Medicine
Liyi Xie: Fudan University Shanghai Cancer Center
Qian Huang: Shanghai Jiaotong University School of Medicine
Fang Li: Duke University Medical Center
Chuan-Yuan Li: Duke University Medical Center

Nature, 2020, vol. 588, issue 7839, 693-698

Abstract: Abstract Despite its success in achieving the long-term survival of 10–30% of treated individuals, immune therapy is still ineffective for most patients with cancer1,2. Many efforts are therefore underway to identify new approaches that enhance such immune ‘checkpoint’ therapy3–5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9—a key protein in the regulation of cholesterol metabolism6–8—can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9’s cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9—either through genetic deletion or using PCSK9 antibodies—increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (7)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2911-7 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:588:y:2020:i:7839:d:10.1038_s41586-020-2911-7

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2911-7

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().