Loss of p14 reduces immunogenicity in melanoma by affecting the peptide surface density via non-canonical Wnt signaling

CDKN2A and its two gene products p14 and p16 are one of the most frequently negatively altered gene loci (either by loss or mutation) in advanced melanoma accompanied by decreased T cell infiltration in melanoma. In this study, we shed light on the connection of the reduction of the CDKN2A gene product p14 and its impact on melanoma immunogenicity. Knockdown of p14 in melanoma cell lines diminishes the recognition and killing by melanoma differentiation antigen (MDA) specific T cells. Resistance was caused by a reduction of surface density of presented differentiation surface antigens. While antigen presentation via HLA-I molecules was enhanced upon p14 downregulation in general, absolute and relative expression of cognate peptides was decreased. Limiting Wnt5a signaling reverted this phenotype showing 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.

细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）及其两种基因产物p14与p16，是晚期黑色素瘤中最常见的发生负向改变的基因位点之一，此类改变可通过基因缺失或突变实现，且常伴随黑色素瘤内部T细胞浸润水平降低。本研究阐明了CDKN2A基因产物p14的表达下调与黑色素瘤免疫原性之间的关联机制。在黑色素瘤细胞系中敲低p14的表达，会削弱黑色素瘤分化抗原（melanoma differentiation antigen, MDA）特异性T细胞对肿瘤细胞的识别与杀伤能力。该抵抗现象的产生，源于肿瘤细胞表面呈递的分化抗原密度降低。尽管总体而言，p14表达下调可增强通过人类白细胞抗原I型（HLA-I）分子完成的抗原呈递过程，但同源肽段的绝对与相对表达量均出现下降。抑制Wnt5a信号通路可逆转这一表型，提示非经典Wnt信号通路参与了该过程。综上，本研究数据揭示了一种全新的机制：通过降低黑色素瘤内MDA肽段的绝对与相对呈递水平，从而抑制MDA特异性T细胞应答。