Liao Yuan, Yao Wenxia, Liu Zhaoyu, Peng Qian, Zhou Xinke, Xie Mengyuan, Mai Zesen
Department of Dermatology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Innovation Centre for Advanced Interdisciplinary Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Autoimmunity. 2025 Dec;58(1):2531833. doi: 10.1080/08916934.2025.2531833. Epub 2025 Jul 15.
Melanoma is a malignant tumor with limited treatment option in advanced stages. Apolipoprotein L3 (APOL3), a protein implicated in immune regulation, has recently emerged as a potential player in tumor immunity. This research aims to explore the potential efficacy of APOL3 in melanoma. Using data from the Cancer Genome Atlas-Skin Cutaneous Melanoma (TCGA-SKCM), we identified two clusters based on 56 prognostic antigen presentation-related genes. Differential expression analysis revealed 185 genes between these two clusters, which were further narrowed down to 34 genes using univariate analysis and random survival forest dimensionality reduction. Among them, APOL3 was found to be the top-ranked gene. Afterward, the effect of APOL3 on melanoma cells was evaluated using CCK-8, EdU, and Transwell experiment. The results showed that overexpression of APOL3 decreases melanoma cell viability, clonogenicity, proliferation, migration, and invasion. Bioinformatics analysis showed the association of high/low APOL3 expression with genomic mutations characterizing melanoma. APOL3 was also found associated with T-cell infiltration levels, immune checkpoints (CD274, PDCD1, CD247, PDCD1LG2, CTLA4, TNFRSF9, TNFRSF4, and TLR9), and some immune pathways. To validate the role of APOL3 on T cell immunity, we applied B16 melanoma cells to construct the mice tumor models. The model showed that APOL3 overexpression markedly reduces melanoma tumor volume and weight while increasing interferon-γ (IFN-γ), granzyme B production, and CD3 T cell infiltration. In conclusion, antigen presentation-related APOL3 promotes anti-tumor T-cell immunity and suppresses melanoma cell growth and in a murine model. These results suggested that APOL3 may serve as a promising immunotherapeutic target for the treatment of melanoma.
黑色素瘤是一种晚期治疗选择有限的恶性肿瘤。载脂蛋白L3（APOL3）是一种与免疫调节有关的蛋白质，最近已成为肿瘤免疫中的一个潜在参与者。本研究旨在探讨APOL3在黑色素瘤中的潜在疗效。利用来自癌症基因组图谱-皮肤黑色素瘤（TCGA-SKCM）的数据，我们基于56个与预后抗原呈递相关的基因鉴定出两个簇。差异表达分析揭示了这两个簇之间的185个基因，使用单变量分析和随机生存森林降维将其进一步缩小到34个基因。其中，APOL3被发现是排名最高的基因。随后，使用CCK-8、EdU和Transwell实验评估APOL3对黑色素瘤细胞的影响。结果表明，APOL3的过表达降低了黑色素瘤细胞的活力、克隆形成能力、增殖、迁移和侵袭。生物信息学分析显示APOL3高/低表达与黑色素瘤的基因组突变特征相关。还发现APOL3与T细胞浸润水平、免疫检查点（CD274、PDCD1、CD247、PDCD1LG2、CTLA4、TNFRSF9、TNFRSF4和TLR9）以及一些免疫途径有关。为了验证APOL3对T细胞免疫的作用，我们应用B16黑色素瘤细胞构建小鼠肿瘤模型。该模型显示，APOL3的过表达显著降低了黑色素瘤的肿瘤体积和重量，同时增加了干扰素-γ（IFN-γ）、颗粒酶B的产生以及CD3 T细胞浸润。总之，在小鼠模型中，与抗原呈递相关的APOL3促进抗肿瘤T细胞免疫并抑制黑色素瘤细胞生长。这些结果表明，APOL3可能是治疗黑色素瘤的一个有前景的免疫治疗靶点。
