Effects of immunisation against PCSK9 in mice bearing melanoma

Abstract

Introduction: Inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) is an established modality for the treatment of hypercholesterolaemia. However, the impact of PCSK9 inhibition in other situations such as cancer remains largely unknown. The current study was conducted to study the effects of PCSK9 inhibition on cancer endpoints in mice bearing melanoma. Material and methods: To generate antiPCSK9 antibody in vivo, a nanoliposomal antiPCSK9 vaccine adsorbed to 0.4% Alum adjuvant was subcutaneously injected in C57BL/6 mice four times with biweekly intervals. Two weeks after the last immunisation, mice were subcutaneously inoculated with B16F0 melanoma cells. After a tumour mass was palpable (approximately 10 mm 3), the mice were randomly divided into four groups and subjected to different treatment protocols: (1) PBS (untreated control), (2) vaccine group, (3) the combination of vaccine and a single dose of liposomal doxorubicin (Doxil ®), and (4) liposomal doxorubicin (positive control) group. To determine therapeutic efficacy, mouse body weight, tumour size, and survival were monitored every three days for 36 days. Results: The nanoliposomal antiPCSK9 vaccine was found to efficiently induce specific antibodies against PCSK9 in C57BL/6 mice, thereby reducing plasma levels and function of PCSK9. Tumour volumes in the vaccinated group were not significantly different from those in the liposomal doxorubicin, combination, and control groups. The time to reach endpoint (TTE) values of the vaccine (28 ±5 days), combination (30 ±6 days), liposomal doxorubicin (34 ±2 days), and control (31 ±2 days) groups were not significantly different, either. Furthermore, the tumour growth delay (TGD) values of the vaccine (-11.5 ±15.4%), liposomal doxorubicin (7.75 ±6.5%), combination (-6 ±20.77%), and control (0 ±7.5) groups were not significantly different. Finally, there was no significant difference between the median survival time and lifespan of the vaccinated versus other tested groups.

Pro-protein convertase subtilisin/kexin type 9 promotes intestinal tumor development by activating Janus kinase 2/signal transducer and activator of transcription 3/SOCS3 signaling in ApcMin/+ mice

“…14 Over the past 10 years, a considerable amount of literature has accumulated on the role of PCSK9 in hypercholesterolemia and human malignancies. 35,36 Recently, researchers have begun to assess anti-PCSK9 vaccines against breast cancer and melanoma in mice, 34,37 and a previous study reported that a nano liposomal anti-PCSK9 vaccine has potential anti-tumor effect in colorectal cancer. 14 This study directly linked PCSK9 with the development and progression of mouse adenomas and adenocarcinomas in transgenic mice, supporting previous studies which examined an anti-PCSK9 vaccine against colorectal cancer.…”

“…PCSK9 has multiple biological functions, including regulation of cell apoptosis and the tissue inflammation response, in addition to regulating blood lipid in vivo. 30,31 The inhibition of PCSK9 induced the apoptosis of the lung cancer cells, A549, and the glioma cells, U251, 32,33 prevented liver metastasis in mice with melanoma, 34 and prolonged the survival of BALB/c mice inoculated with the colon cancer cells, CT26. 14 Over the past 10 years, a considerable amount of literature has accumulated on the role of PCSK9 in hypercholesterolemia and human malignancies.…”

PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity

“…Nevertheless, this reveals that the inhibition of PCSK9 by vaccination had no side effects on the breast tumor endpoint and that it could improve breast cancer behavior [ 152 ]. On the other hand, vaccination with L-IFPTA + vaccine in mice bearing melanoma did not show any effect on tumor growth nor the survival of tumor-bearing mice [ 153 ]. Here again, the same peptide-based vaccine only bound 50% of circulating mouse PCSK9.…”

PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity

“…Proprotein convertase subtilisin kexin type 9 (PCSK9) is a major regulator of cholesterol homeostasis via binding and downregulating low-density lipoprotein receptor (LDLR) [ 21 – 25 ]. PCSK9 displays oncogenic actions in cancer [ 26 ], including gastric cancer [ 27 ], esophageal cancer [ 28 ], prostate cancer [ 29 – 31 ], breast cancer [ 32 ], ovarian cancer [ 33 ], lung cancer [ 34 – 37 ], hepatocellular carcinoma [ 38 , 39 ], and melanoma [ 40 , 41 ]. While accumulative evidence reveals a general action of PCSK9 in facilitating tumorigenesis, the specific association of PCSK9’s role in regulating lipid metabolism and its oncogenic potential remains unclear.…”

“…Considering the strong evidence for PCSK9’s oncogenic involvement, it is surprising that PCSK9 vaccine has no impact on melanoma and only modestly reduces breast cancer growth in murine models [ 32 , 40 ]. This may be related to the relative inefficiencies of the reported vaccines to completely block PCSK9 activity.…”