PCSK9, also known as proprotein convertase subtilisin/kexin type 9, is a proteolytic enzyme that plays a pivotal role in lipid metabolism. It indirectly regulates serum LDL cholesterol (LDL-C) by causing the destruction of LDL receptors on the surface of liver hepatocytes. This regulation of LDL-C levels is crucial for cardiovascular health [1,3,4].

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 targeted at the checkpoint protein PD1. This shows that inhibiting PCSK9 can boost the response of tumours to immune checkpoint therapy through a mechanism independent of its cholesterol-regulating functions [2].

In conclusion, PCSK9 is essential in regulating LDL-C levels, thus having a significant impact on cardiovascular health. The gene knockout mouse models have revealed an unexpected role of PCSK9 in cancer, specifically in modulating the response to immune checkpoint therapy. These findings suggest that PCSK9 could be a potential target for enhancing cancer immunotherapy as well as treating hypercholesterolemia-related cardiovascular diseases [1,2,3,4].

References:

1. Roth, Eli M, Davidson, Michael H. . PCSK9 Inhibitors: Mechanism of Action, Efficacy, and Safety. In Reviews in cardiovascular medicine, 19, S31-S46. doi:10.3909/ricm19S1S0002. https://pubmed.ncbi.nlm.nih.gov/30207556/

2. 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/

3. Melendez, Quantil M, Krishnaji, Sreevidhya T, Wooten, Catherine J, Lopez, Dayami. 2017. Hypercholesterolemia: The role of PCSK9. In Archives of biochemistry and biophysics, 625-626, 39-53. doi:10.1016/j.abb.2017.06.001. https://pubmed.ncbi.nlm.nih.gov/28587771/

4. Blanchard, Valentin, Khantalin, Ilya, Ramin-Mangata, Stéphane, Nativel, Brice, Lambert, Gilles. 2018. PCSK9: from biology to clinical applications. In Pathology, 51, 177-183. doi:10.1016/j.pathol.2018.10.012. https://pubmed.ncbi.nlm.nih.gov/30522786/