RESUMEN
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9), the last member of the proprotein convertase family, functions as a classic regulator of low-density lipoprotein (LDL) by interacting with low-density lipoprotein receptor (LDLR). Recent studies have shown that PCSK9 can affect the occurrence and development of tumors and can be used as a novel therapeutic target. However, a comprehensive pan-cancer analysis of PCSK9 has yet to be conducted. METHODS: The potential oncogenic effects of PCSK9 in 33 types of tumors were explored based on the datasets of The Cancer Genome Atlas (TCGA) dataset. In addition, the immune regulatory role of PCSK9 inhibition was evaluated via in vitro cell coculture and the tumor-bearing mouse model. Finally, the antitumor efficacy of targeted PCSK9 combined with OVA-II vaccines was verified. RESULTS: Our results indicated that PCSK9 was highly expressed in most tumor types and was significantly correlated with late disease stage and poor prognosis. Additionally, PCSK9 may regulate the tumor immune matrix score, immune cell infiltration, immune checkpoint expression, and major histocompatibility complex expression. Notably, we first found that dendritic cell (DC) infiltration and major histocompatibility complex-II (MHC-II) expression could be upregulated by PCSK9 inhibition and improve CD8+ T cell activation in the tumor immune microenvironment, thereby achieving potent tumor control. Combining PCSK9 inhibitors could enhance the efficacies of OVA-II tumor vaccine monotherapy. CONCLUSIONS: Conclusively, our pan-cancer analysis provided a more comprehensive understanding of the oncogenic and immunoregulatory roles of PCSK9 and demonstrated that targeting PCSK9 could increase the efficacy of long peptide vaccines by upregulating DC infiltration and MHC-II expression on the surface of tumor cells. This study reveals the critical oncogenic and immunoregulatory roles of PCSK9 in various tumors and shows the promise of PCSK9 as a potent immunotherapy target.
Asunto(s)
Genes MHC Clase II , Inmunoterapia , Neoplasias , Proproteína Convertasa 9 , Proproteína Convertasas , Animales , Ratones , Antígenos de Histocompatibilidad , Lipoproteínas LDL , Neoplasias/genética , Neoplasias/terapia , Proproteína Convertasa 9/metabolismo , Proproteína Convertasas/antagonistas & inhibidores , Receptores de LDL/genética , Microambiente TumoralRESUMEN
Planteamos un paciente de 62 años que precisa tratamiento hipolipemiante con inhibidor de la proproteína convertasa subtilisina/kexina tipo9 (PCSK9) en el que empíricamente decidimos cambiar un fármaco a otro de los dos disponibles en la actualidad, obteniendo diferente respuesta. Nuestro objetivo es transmitir nuestra experiencia y reflexionar sobre una posible opción terapéutica en los pacientes en los que excepcionalmente esto pudiera ocurrir
The case is presented of a 62-year-old patient who required lipid-lowering therapy with proprotein convertase subtilisin/kexin type9 (PCSK9). It was empirically decided to change one drug to another of the two currently available, obtaining a different response. Our objective is to present our experience and to consider a possible therapeutic option in patients in whom, exceptionally, this could happen
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Proproteína Convertasa 9/administración & dosificación , Proproteína Convertasas/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Hipercolesterolemia/tratamiento farmacológico , Presión Arterial/efectos de los fármacos , Proproteína Convertasas/metabolismo , Índice de Masa Corporal , Lipoproteínas LDL/efectos de los fármacosRESUMEN
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