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. 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. 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. 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.

中文翻译：

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肿瘤免疫治疗中靶向PCSK9上调肿瘤细胞表面MHC-II

前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 是前蛋白转化酶家族的最后一个成员，通过与低密度脂蛋白受体 (LDLR) 相互作用，充当低密度脂蛋白 (LDL) 的经典调节剂。最近的研究表明PCSK9可以影响肿瘤的发生和发展，可以作为新的治疗靶点。然而，尚未对 PCSK9 进行全面的泛癌分析。基于癌症基因组图谱（TCGA）数据集的数据集探讨了 PCSK9 在 33 种肿瘤中的潜在致癌作用。此外，通过体外细胞共培养和荷瘤小鼠模型评估了 PCSK9 抑制的免疫调节作用。最后验证了靶向PCSK9联合OVA-II疫苗的抗肿瘤功效。我们的结果表明，PCSK9 在大多数肿瘤类型中高表达，并且与晚期疾病阶段和不良预后显着相关。此外，PCSK9 还可以调节肿瘤免疫基质评分、免疫细胞浸润、免疫检查点表达和主要组织相容性复合物表达。值得注意的是，我们首次发现抑制PCSK9可以上调树突状细胞（DC）浸润和主要组织相容性复合物-II（MHC-II）表达，并改善肿瘤免疫微环境中CD8+ T细胞的活化，从而实现有效的肿瘤控制。联合PCSK9抑制剂可以增强OVA-II肿瘤疫苗单一疗法的疗效。总之，我们的泛癌分析提供了对 PCSK9 的致癌和免疫调节作用的更全面的了解，并证明靶向 PCSK9 可以通过上调 DC 浸润和肿瘤细胞表面 MHC-II 表达来提高长肽疫苗的功效。这项研究揭示了 PCSK9 在各种肿瘤中的关键致癌和免疫调节作用，并显示了 PCSK9 作为有效免疫治疗靶点的前景。