Current Understanding of PCSK9 and Its Relevance to Cancer Prognosis and Immune Therapy: A Review

Abstract

The effectiveness of immunotherapy for most cancer patients remains low, with approximately 10-30% of those treated surviving. Thus, much effort is being put into finding new ways to improve immune checkpoint therapy. Our review concludes that inhibition of proprotein convertase subtilisin/Kexin type 9 (PCSK9), which plays a critical role in regulating cholesterol metabolism, can cause movement of T cells toward tumors, with increased sensitivity to immune checkpoint therapies. We searched PubMed, NCBI, Scopus, and Google Scholar for the published articles without limitations on publication dates. We used the following terms: "PCSK9", "Cancer", "Immune Checkpoint", and "Cancer Prognosis" in the title and/or abstract. Our search initially revealed 600 records on the subject and stored them in the used databases under EndNote X8 management software. A total of 161 articles were selected and through a careful review, 76 were included in our research. We concluded that PCSK9 reduces the number of LDL receptors (LDL-R) on the cell surface, which is linked to its ability to regulate cholesterol levels in the body. Also, we discuss how suppressing PCSK9 leads to the MHC-1 accumulation on the surface of cancer cells, which results in T lymphocyte invasion. Finally, we believe that inhibiting PCSK9 may be an effective strategy for improving cancer immunotherapy.

Keywords: Cancer; Immune checkpoint; Immunotherapy; PCSK9.

Fig. 1

A. Role of PCSK9 in increasing cholesterol availability for cancer cells (24). B. In tumor cells, upon binding to MHC I, PCSK9 mediates degradation via the endosomal/lysosomal pathway, preventing its recycling to the surface

Fig. 2

The schematic representation effect of LPS on PCSK9 in HCC (32, 36, 37).

Fig. 3

T cells attack tumor cells by binding to antigens on MHC-I molecules on their surfaces, initiating the adaptive immune response. On the other hand, with the connection of PD1 and anti-PD1 antibodies, the possibility of immunosuppression is neutralized. Both of these functions increase the anti-cancer effect. As a result of PCSK9 inhibition, T cells infiltrate the tumor, making it susceptible to immune checkpoint therapy (23, 58).