免疫疗法在黑色素瘤治疗中取得了巨大成功。然而，只有约 50% 的晚期黑色素瘤患者从免疫治疗中受益。细胞周期蛋白依赖性激酶抑制剂 2A (CDKN2A) 编码两种肿瘤抑制蛋白 p14ARF 和 p16INK4a，属于黑色素瘤中最常失活的基因位点，可导致 T 细胞浸润减少。虽然 p16INK4a 的作用已被广泛研究，但有关 p14ARF 在黑色素瘤中的知识却很少。在这项研究中，我们阐明了 p14ARF 表达减少对黑色素瘤免疫原性的影响。黑色素瘤细胞系中 p14ARF 的敲低会减弱黑色素瘤分化抗原 (MDA) 特异性 T 细胞对它们的识别和杀伤。耐药性是由于所呈现的 MDA 的肽表面密度降低而引起的。免疫肽组学分析表明，p14ARF 下调后，通过人白细胞 I 类抗原 (HLA-I) 分子的抗原呈递通常会增强，但同源肽的绝对和相对表达会降低。然而，这种表型与黑色素瘤患者的良好结果相关。限制 Wnt5a 信号传导可恢复这种表型，表明涉及非经典 Wnt 信号传导。总而言之，我们的数据表明了一种通过减少黑色素瘤中绝对和相对 MDA 肽呈现来限制 MDA 特异性 T 细胞反应的新机制。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Immunotherapy has achieved tremendous success in melanoma. However, only around 50% of advanced melanoma patients benefit from immunotherapy. Cyclin-dependent kinase inhibitor 2A (CDKN2A), encoding the two tumor-suppressor proteins p14ARF and p16INK4a, belongs to the most frequently inactivated gene loci in melanoma and leads to decreased T cell infiltration. While the role of p16INK4a has been extensively investigated, knowledge about p14ARF in melanoma is scarce. In this study, we elucidate the impact of reduced p14ARF expression on melanoma immunogenicity. Knockdown of p14ARF in melanoma cell lines diminished their recognition and killing by melanoma differentiation antigen (MDA)-specific T cells. Resistance was caused by a reduction of the peptide surface density of presented MDAs. Immunopeptidomic analyses revealed that antigen presentation via human leukocyte antigen class I (HLA-I) molecules was enhanced upon p14ARF downregulation in general, but absolute and relative expression of cognate peptides was decreased. However, this phenotype is associated with a favorable outcome for melanoma patients. Limiting Wnt5a signaling reverted this phenotype, suggesting an involvement of non-canonical Wnt signaling. Taken together, our data indicate a new mechanism limiting MDA-specific T cell responses by decreasing both absolute and relative MDA-peptide presentation in melanoma.© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.