Pcsk9-KO Mouse

Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy targeted at the checkpoint protein PD1. 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, 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 [1].

In conclusion, PCSK9 is a key regulator of LDL-C levels through its impact on LDL receptor degradation. The gene knockout mouse models have revealed its unexpected role in enhancing cancer immune checkpoint therapy, suggesting PCSK9 as a potential target not only for hypercholesterolemia-related cardiovascular diseases but also for cancer treatment [1].

References:

1. Liu, Xinjian, Bao, Xuhui, Hu, Mengjie, Li, Fang, Li, Chuan-Yuan. 2020. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. In Nature, 588, 693-698. doi:10.1038/s41586-020-2911-7. https://pubmed.ncbi.nlm.nih.gov/33177715/