Antigen presentation-related protein APOL3 promotes anti-tumor T cell immunity and suppresses melanoma cell growth in mice

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 <i>in-vitro</i> and <i>in-vivo</i> in a murine model. These results suggested that APOL3 may serve as a promising immunotherapeutic target for the treatment of melanoma.