PRAME boosts T-cell tumor immunity in specific HLA phenotypes and promotes breast cancer stemness via CCL18 chemokine signaling

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Background/objective Tumor-associated macrophages (TAMs) and chemokine CCL18 play a pivotal role in breast cancer (BC) metastasis. They also promote breast cancer stem cells (BCSCs) enrichment. The melanoma-associated antigen such as preferentially expressed antigen in Melanoma (PRAME) is abnormally expressed in many cancers and is also associated with BC metastasis, but the specific mechanism is unclear. This study explores the role of PRAME and other tumor-linked antigens in BCSCs and their potential for immunotherapy in specific human leukocytes antigen (HLA) phenotypes. Methods We analyzed 28 BC tissues (non-metastatic: 17; metastatic: 11) via immunohistochemistry (IHC) and Western blot. Bioinformatics profiling of 1102 BC samples (TCGA/Oncomine) assessed CCL18-PRAME-BCSC correlations. In vitro , CCL18-induced BCSC self-renewal (sphere formation) and PRAME upregulation were validated in MCF-7/MDA-MB-231 cells. HLA-A∗11:01 prevalence was determined by PCR/Sanger sequencing. PRAME-derived peptides were screened in silico (NetMHC/EpiJen) and validated in dendritic cell (DC)-T cell co-cultures, with Granzyme B activation measured via Luminex assay. Results CCL18 expression correlated with BCSCs markers (such as CD44+/CD24-/ALDH1A1+) and PRAME in BC tissues. PRAME was significantly upregulated in BCSCs and BC metastasis, increased in human BC under CCL18 induction, and enhanced BCSC self-renewal and metastatic potential. T cells infiltration was activated when PRAME was highly expressed in the HLA-A∗1101 phenotype. In this phenotype, PRAME derived peptides (such as SMSVWTSPR, YVDSLFFLR, and ELFSYLIEK) presented by dendritic cells significantly increased the level of granzyme B and activated T cell immunity against tumor cells. Conclusion The PRAME's interaction with the tumor microenvironment and immune system highlights its potential as a biomarker for BC prognosis and a candidate for targeted immunotherapy, offering new targets for precision medicine in BC treatment. This suggests context-dependent dual functionality of PRAME in both promoting metastasis and enhancing anti-tumor immunity.

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